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| United States Patent |
5,223,522
|
|
Clark
, et al.
|
June 29, 1993
|
Thiazolidinedione hypoglycemic agents
Abstract
Hypoglycemic thiazolidine-2,4-dione derivatives of the formula
##STR1##
wherein the dotted line represents a bond or no bond;
A and B are each independently CH;
X is S, SO, SO.sub.2, CH.sub.2, CHOH or CO;
n is 0 or 1;
Y is CHR.sup.1 or NR.sup.2, with the proviso that when n is 1 and Y is
NR.sup.2, X is SO.sub.2 or CO;
Z is CHR.sup.3, CH.sub.2 CH.sub.2, CH.dbd.CH,
##STR2##
OCH.sub.2, SCH.sub.2, SOCH.sub.2 or SO.sub.2 CH.sub.2 ; R, R.sup.1,
R.sup.2 and R.sup.3 are each independently hydrogen or methyl; and
X.sup.1 and X.sup.2 are each independently hydrogen, methyl,
trifluoromethyl, phenyl, benzyl, hydroxy, methoxy, phenoxy, benzyloxy,
bromo, chloro or fluoro;
a pharmaceutically-acceptable cationic salt thereof; or
a pharmaceutically-acceptable acid addition salt thereof.
| Inventors:
|
Clark; David A. (East Lyme, CT);
Goldstein; Steven W. (Mystic, CT);
Holland; Gerald F. (Old Lyme, CT);
Hulin; Bernard (Essex, CT);
Rizzi; James P. (Waterford, CT)
|
| Assignee:
|
Pfizer Inc. (New York, NY)
|
| Appl. No.:
|
857039 |
| Filed:
|
March 24, 1992 |
| Current U.S. Class: |
514/369; 548/183 |
| Intern'l Class: |
C07D 277/04; A61K 031/425 |
| Field of Search: |
546/280
548/183
514/369
|
References Cited
U.S. Patent Documents
| 4287200 | Sep., 1981 | Kawamatsu et al. | 514/369.
|
| 4517312 | Oct., 1986 | Schnur | 514/369.
|
| 4703052 | Oct., 1987 | Eggler et al. | 514/337.
|
| 4725610 | Feb., 1988 | Meguro et al. | 514/369.
|
| 4775687 | Oct., 1988 | Meguro et al. | 514/369.
|
| 5120754 | Jun., 1992 | Clark et al. | 514/369.
|
Other References
Burger, Alfred, Medicinal Chemistry, vol. 3, 3rd Ed., pp. 64-80,
Wiley-Interscience (1970).
Sohda et al., Chem. Pharm. Bull Japan, vol. 30, pp. 3580-3600 (1982)
Chemical Abstracts 80:168259k (abstracting Japan Kokai 80-64586).
|
Primary Examiner: Rotman; Alan L.
Attorney, Agent or Firm: Richardson; Peter C., Benson; Gregg C., Brokke; Mervin E.
Parent Case Text
This is a division of co-pending application Ser. No. 07/679,898, filed on
Apr. 3, 1991 now U.S. Pat. No. 5,120,756, which is a division of
application Ser. No. 07/566,436, now U.S. Pat. No. 5,061,717 filed on Aug.
14, 1990; as a request for U.S. examination of International Application
No. PCT/US88,00744, filed Mar. 8, 1998.
Claims
We claim:
1. A compound having the formula
##STR12##
wherein the dotted line represents a bond or no bond;
A and B are each CH;
X is S, SO, SO.sub.2, CHOH or CO;
n is 0 or 1;
Y is CHR.sup.1 or NR.sup.2, with the proviso that when n is 1 and Y is
NR.sup.2, X is SO.sub.2 or CO;
Z is
##STR13##
OCH.sub.2, SCH.sub.2, SOCH.sub.2 or SO.sub.2 CH.sub.2 ; R, R.sup.1,
R.sup.2 and R.sup.3 are each independently hydrogen or methyl; and
X.sup.1 and X.sup.2 are each independently hydrogen, methyl,
trifluoromethyl, phenyl, benzyl, hydroxy, methoxy, phenoxy, benzyloxy,
bromo, chloro or fluoro; a pharmaceutically-acceptable cationic salt
thereof; or a pharmaceutically-acceptable acid addition salt thereof.
2. A compound of claim 1 wherein the dotted line represents no bond, X is
CO, n is O and R is hydrogen.
3. A pharmaceutical composition which comprises an effective blood glucose
lowering amount of a compound of claim 1 and a pharmaceutically-acceptable
carrier.
4. A method of lowering blood glucose in a hyperglycemic mammal which
comprises administering to said mammal a blood glucose lowering effective
amount of a compound of claim 1.
5. A pharmaceutical composition which comprises an effective blood
cholesterol lowering amount of a compound of claim 1 and a
pharmaceutically-acceptable carrier.
6. A method of lowering blood cholesterol in a hypercholesterolemic mammal
which comprises administering to said mammal a blood cholesterol lowering
effective amount of a compound of claim 1.
Description
BACKGROUND OF THE INVENTION
The present invention relates to certain compounds of the formula (I),
depicted below, having utility as hypoglycemic and hypocholesterolemic
agents, methods for their use and pharmaceutical compositions containing
them.
In spite of the early discovery of insulin and its subsequent wide-spread
use in the treatment of diabetes, and the later discovery and use of
sulfonylureas (e.g. chlorpropamide, tolbutamide, acetohexamide,
tolazamide) and biguanides (e.g. phenformin) as oral hypoglycemic agents,
the treatment of diabetes remains less than satisfactory. The use of
insulin, necessary in about 10% of diabetic patients in which synthetic
hypoglycemic agents are not effective (Type I diabetes, insulin dependent
diabetes mellitus), requires multiple daily doses, usually by self
injection. Determination of the proper dosage of insulin requires frequent
estimations of the sugar in the urine or in the blood. The administration
of an excess dose of insulin causes hypoglycemia, with effects ranging
from mild abnormalities in blood glucose or coma, or even death. Treatment
of non-insulin dependent diabetes mellitus (Type II diabetes) usually
consists of a combination of diet, exercise, oral agents, e.g.,
sulfonylureas, and in more severe cases, insulin. However, the clinically
available hypoglycemics are unfortunately fraught with other toxic
manifestations which limit their use. In any event, where one of these
agents may fail in an individual case, another may succeed. A continuing
need for hypoglycemic agents, which may be less toxic or succeed where
others fail, is clearly evident.
Furthermore, atherosclerosis, a disease of the arteries, is recognized to
be the leading cause of death in the United States and Western Europe. The
pathological sequence leading to atherosclerosis and occlusive heart
disease has been described in detail by Ross and Glomset in New England
Journal of Medicine 295, 369-377 (1976). The earliest stage in this
sequence is the formation of "fatty streaks" in the carotid, coronary and
cerebral arteries and in the aorta. These lesions are yellow in color due
to the presence of lipid deposits found principally within smooth-muscle
cells and in macrophages of the intima layer of the arteries and aorta.
Cholesterol and cholesteryl ester account for most of this lipid. Further,
it is postulated that most of the cholesterol found within the fatty
streaks results from uptake from the plasma. These fatty streaks, in turn,
give rise to development of the "fibrous plaque," which consists of
accumulated intimal smooth muscle cells laden with lipid and surrounded by
extra cellular lipid, collagen, elastin and proteoglycans. The cells plus
matrix form a fibrous cap that covers a deeper deposit of cell debris and
more extracellular lipid. The lipid is primarily free and esterified
cholesterol. The fibrous plaque forms slowly, and is likely in time to
become calcified and necrotic, advancing to the "complicated lesion" which
accounts for the arterial occlusion and tendence toward mural thrombosis
and arterial muscular spasm that characterize advanced atherosclerosis.
Epidemiological evidence has firmly established hyperlipidemia as a primary
risk factor in causing cardiovascular disease (CVD) due to
atherosclerosis. In recent years, leaders of the medical profession have
placed renewed emphasis on lowering plasma cholesterol levels, and low
density lipoprotein cholesterol in particular, as an essential step in
prevention of CVD. The upper limits of "normal" are now known to be
significantly lower than heretofore appreciated. As a result, large
segments of Western populations are now realized to be at high risk for
development or progression of CVD because of this factor. Individuals who
possess independent risk factors in addition to hyperlipidemia are at
particularly high risk. Such independent risk factors include glucose
intolerance, left ventricular hypertrophy hypertension, and being of the
male sex. Cardiovascular disease is especially prevalent among diabetic
subjects, at least in part because of the existence of multiple
independent risk factors. Successful treatment of hyperlipidemia in the
general population, and in diabetic subjects in particular, is therefore
of exceptional medical importance.
The first step in recommended therapeutic regimens for hyperlipidemia is
dietary intervention. While diet alone produces adequate response in some
individuals, many others remain at high risk and must be treated further
by pharmacological means. New drugs for the treatment of hyperlipidemia
are, therefore, of great potential benefit for large numbers of
individuals at high risk of developing CVD. Further, successful treatment
of both the hyperlipidemia and hyperglycemia associated with the diabetic
state with a single therapeutic agent is particularly desirable.
In addition to the hypoglycemic agents cited above, a variety of other
compounds have been reported to possess this type of activity, as reviewed
by Blank [Burger's Medicinal Chemistry, Fourth Edition, Part II, John
Wiley and Sons, N.Y. (1979), pp. 1057-1080].
Schnur, U.S. Pat. No. 4,367,234 discloses hypoglycemic oxazolidinediones of
the formula
##STR3##
in which the phenyl ring is generally mono- or multi-substituted in the
ortho/meta positions. Notably, with the exception of the 4-fluorophenyl
analog, the para-substituted derivatives are either inactive or possess a
low level of hypoglycemic activity.
Schnur, U.S. Pat. No. 4,342,771 discloses oxazolidinedione hypoglycemic
agents of the formula
##STR4##
limited to compounds in which Y is hydrogen or alkoxy, Y' is hydrogen or
alkyl and Y" is hydrogen or halo.
Schnur, U.S. Pat. No. 4,617,312 discloses hypoglycemic thiazolidinediones
of the formula
##STR5##
where R.sup.c is lower alkyl, X.sup.a is F, Cl or Br, and Y.sup.a is
hydrogen, chloro, lower alkyl or lower alkoxy. Notably, the compounds
require ortho-substitution with an alkoxy group, and para-substitution is
limited to hydrogen or halogen.
Kawamatsu et al., U.S. Pat. No. 4,340,605 disclose hypoglycemic compounds,
also having plasma triglyceride lowering activity, of the formula
##STR6##
wherein R.sup.e is a bond or lower alkylene and when R.sup.d is optionally
substituted phenyl, L.sup.1 and L.sup.2 may each be defined as hydrogen.
Based on a lack of hypoglycemic and plasma triglyceride lowering activity
of certain non-ether analogs, it has been suggested that the boxed portion
of the structural formula, which includes the ether oxygen, represents an
essential feature for useful activity in this series of compounds; Sohda
et al., Chem. Pharm. Bull, Japan, vol. 30, pp. 3580-3600 (1982).
Eggler et al., U.S. Pat. No. 4,703,052, discloses hypoglycemic
thiazolidinediones of the formula
##STR7##
where the dotted line represents an optional bond, R.sup.f is H, methyl or
ethyl, X.sup.b is O, S, SO, SO.sub.2, CH.sub.2, CO, CHOH or NR.sup.k,
R.sup.k is H or an acyl group and the numerous definitions of R.sup.g,
R.sup.h, R.sup.i and R.sup.j include R.sup.g, R.sup.h and R.sup.i as
hydrogen or methyl and R.sup.j as optionally substituted phenyl, benzyl,
phenethyl or styryl.
SUMMARY OF THE INVENTION
The present invention is directed to compounds having the formula
##STR8##
wherein the dotted line represents a bond or no bond;
A and B are each independently CH or N, with the proviso that when A or B
is N, the other is CH;
X is S, SO, SO.sub.2, CH.sub.2, CHOH or CO;
n is 0 or 1;
Y is CHR.sup.1 or NR.sup.2, with the proviso that when n is 1 and Y is
NR.sup.2, X is SO.sub.2 or CO;
Z is CHR.sup.3, CH.sub.2 CH.sub.2, CH.dbd.CH,
##STR9##
OCH.sub.2, SCH.sub.2, SOCH.sub.2 or SO.sub.2 CH.sub.2 ; R, R.sup.1,
R.sup.2 and R.sup.3 are each independently hydrogen or methyl; and
X.sup.1 and X.sup.2 are each independently hydrogen, methyl,
trifluoromethyl, phenyl, benzyl, hydroxy, methoxy, phenoxy, benzyloxy,
bromo, chloro or fluoro;
a pharmaceutically-acceptable cationic salt thereof; or
a pharmaceutically-acceptable acid addition salt thereof when A or B is N.
The preferred compounds are:
a) those wherein the dotted line represents no bond, A and B are each CH, X
is CO, n is 0, R is hydrogen, Z is CH.sub.2 CH.sub.2 or CH.dbd.CH and
X.sup.2 is hydrogen, particularly when X.sup.1 is hydrogen, 2-methoxy,
4-benzyloxy or 4-phenyl;
b) those wherein A and B are each CH, X is S or SO.sub.2, n is 0, R is
hydrogen, Z is CH.sub.2 CH.sub.2 and X.sup.2 is hydrogen, particularly
when X.sup.1 is hydrogen or 4-chloro.
The expression "pharmaceutically-acceptable cationic salts" is intended to
define but not limited to such salts as the alkali metal salts, (e.g.
sodium and potassium), alkaline earth metal salts (e.g. calcium and
magnesium), aluminum salts, ammonium salts, and salts with organic amines
such as benzathine (N,N'-dibenzylethylenediamine), choline,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine),
benethamine (N-benzylphenethylamine) diethylamine, piperazine,
tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol) and procaine. An
especially preferred such salt is the sodium salt.
The expression "pharmaceutically-acceptable acid addition salts" is
intended to define but not limited to such salts as the hydrochloride,
hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate,
dihydrogenphosphate, acetate, succinate, citrate, methanesulfonate
(mesylate) and p-toluenesulfonate (tosylate) salts.
Also embraced by the present invention are pharmaceutical compositions for
use in treating a hyperglycemic mammal or a hypercholesterolemic mammal
which comprises a blood glucose lowering amount or a blood cholesterol
lowering amount of a compound of formula (I) and a
pharmaceutically-acceptable carrier. The invention further comprises a
method of lowering blood glucose in a hyperglycemic mammal which comprises
administering to said mammal a blood glucose lowering effective amount of
a compound of formula (I); and a method of lowering blood cholesterol in a
hypercholesterolemic mammal which comprises administering to said mammal a
blood cholesterol lowering amount of a compound of the formula (I).
DETAILED DESCRIPTION OF THE PRESENT INVENTION
The compounds of the formula (I) of the present invention are readily
prepared. Most generally, the compounds of the formula (I) wherein the
dotted line represents a bond are prepared by reaction of
thiazolidine-2,4-dione with an aldehyde or ketone of the formula
##STR10##
wherein A, B, R, X, X.sup.1, X.sup.2, Y, Z and n are as defined above. In
this step, approximately equimolar amounts of the reactants are heated in
the presence of a mild base to provide the olefin of formula (I) wherein
the dotted line represents a bond. When X is C.dbd.O, the carbonyl group
is preferably in protected form, e.g., as a ketal, preferably as the
cyclic ketal formed with ethylene glycol. Examples of suitable mild bases
for the above reaction include the alkali metal and alkaline earth salts
of weak acids such as the (C.sub.1 -C.sub.12)alkyl carboxylic acids and
benzoic acid; alkali metal and alkaline earth carbonates and bicarbonates
such as calcium carbonate, magnesium carbonate, potassium bicarbonate; and
tertiary amines such as pyridine, N-methylmorpholine, N-ethylpiperidine
and the like. An especially preferred mild base is sodium acetate for
reasons of economy and efficiency.
While this step may be carried out in the presence of a reaction-inert
solvent, it is preferably carried out in the absence of solvent with
excess sodium acetate as the base at a temperature which is sufficiently
high to cause at least partial melting of the reaction mixture. A
preferred such temperature is in the range of from 100.degree. to
250.degree. C., and especially preferred is a temperature of from
140.degree. to 180.degree. C. Usually a 10-25% molar excess of one of the
two reactants is employed, in order to force the reaction to completion
within a reasonable period of time, generally less than 1 or 2 hours. In
the present instance, it is generally preferred to use the readily
available thiazolidine-2,4-dione in excess.
As used here and elsewhere herein, the expression "reaction inert solvent"
refers to a solvent which does not interact with starting materials,
reagents, intermediates or products in a manner which adversely affects
the yield of the desired product.
In a typical such reaction the aldehyde or ketone starting material (II)
and thiazolidinedione are intimately mixed with a molar excess, preferably
a 2-4 fold molar excess, of anhydrous sodium acetate and the mixture is
heated at a temperature high enough to effect melting, generally about
140.degree.-170.degree. C., at which temperature the reaction is
substantially complete in from about 5 to 60 minutes. The desired olefin
of formula (I) wherein the dotted line represents a bond is then isolated,
for example, by mixing with water and filtration, to obtain the crude
product, which is purified, if desired, e.g., by crystallization or by
standard chromatographic methods.
Particularly when R is hydrogen, an alternative preferred method is to
couple a compound of the formula (II) with thiazolidine-2,4-dione in the
presence of a catalytic amount of a secondary amine, preferably
pyrrolidine or piperidine, usually about 0.05 to 0.20 molar equivalents,
in a reaction-inert solvent such as a lower alkanol (e.g., methanol,
ethanol, n-propanol, isopropanol). In this case temperature is not
especially critical, but will generally be above room temperature but
below 100.degree. C. Reflux temperature of the lower alkanol solvent is
particularly convenient.
These olefinic products are active hypoglycemic agents, but also serve as
intermediates for preparation of the corresponding reduced compounds of
formula (I) wherein the dotted line represents no bond. While the
reduction of the above olefins may be carried out by employing a wide
variety of reducing agents which are known to reduce carbon-to-carbon
double bonds, the preferred methods employ hydrogen in the presence of a
noble metal catalyst, zinc in acetic acid, or sodium amalgam or magnesium
metal in methanol. When X is CO, hydrogenation over Pd/C in
tetrahydrofuran under mild conditions is preferred.
When the reduction step is carried out employing hydrogen in the presence
of a noble metal catalyst, a convenient method for carrying out this
transformation is to stir or shake a solution of the olefinic compound of
the formula (I) wherein the dotted line represents a bond in a
reaction-inert solvent under an atmosphere of hydrogen, or hydrogen mixed
with an inert diluent such as nitrogen, in the presence of a noble metal
hydrogenation catalyst. Suitable solvents for this reaction are those
which substantially dissolve the starting compound but which do not
themselves suffer hydrogenation or hydrogenolysis. Examples of such
solvents include ethers such as diethyl ether, tetrahydrofuran, dioxane
and 1,2-dimethoxyethane; low molecular weight amides such an
N,N-dimethylformamide, N-N-dimethylacetamide and N-methylpyrrolidone; and
lower alkyl carboxylic acids such as formic, acetic, propionic and
isobutyric acid. Especially preferred such solvents are tetrahydrofuran
and glacial acetic acid.
Introduction of the hydrogen gas into the reaction medium is usually
accomplished by carrying out the reaction in a sealed vessel containing
the olefinic compound, solvent, catalyst and hydrogen. The pressure inside
the reaction vessel can vary from about 1 to about 100 kg/cm.sup.2. The
preferred pressure range, when the atmosphere inside the reaction vessel
is substantially pure hydrogen, is from about 2 to about 5 kg/cm.sup.2.
The hydrogenation is generally run at a temperature of from about
0.degree. to about 60.degree. C., and preferably from about 25.degree. to
about 50.degree. C. Utilizing the preferred temperature and pressure
values, hydrogenation generally takes place in a few hours, e.g., from
about 2 hours to about 20 hours. The preferred noble metal catalysts used
in this hydrogenation reaction are the type of agents known in the art for
this kind of transformation; for example, palladium, platinum and rhodium.
A palladium catalyst is preferred because such catalysts are not readily
poisoned by sulfur. The catalyst is usually present in an amount from
about 0.01 to about 25 weight-percent, and preferably from about 0.1 to
about 10 weight-percent, based on the olefinic compound. It is often
convenient to suspend the catalyst on an inert support; a particularly
convenient catalyst is palladium suspended on an inert support such as
carbon.
When in the olefinic compound X is carbonyl (or the protected ketal form
thereof) or carbinol (CHOH), hydrogenation under more vigorous conditions
will generally not only produce the compound of the formula (I) wherein
the dotted line no longer represents a bond, but also wherein X is
methylene.
When the hydrogenation of the methylene double bond (and when desired,
other groups) is substantially complete, the desired product of formula
(I) wherein the dotted line is no bond is then isolated by standard
methods, e.g., the catalyst is recovered by filtration, the solvent
evaporated and the product purified, if desired, by well known methods
such as crystallization or by chromatography.
Ketal protecting groups are readily removed by conventional acid catalyzed
hydrolysis, as exemplified below, to form those compounds of the formula
(I) wherein X is C.dbd.O.
Another preferred method for reduction of the olefinic compounds of the
formula (I) wherein the dotted line represents a bond is conventional
sodium amalgam, usually at or about ambient temperature, as exemplified
below. When X is CO, sodium amalgam will generally also reduce this group
to CHOH.
Another preferred method for reducing the olefinic double bond when present
in the compound of the formula (I) is zinc in acetic acid, particularly
valuable when the side chain contains no group (e.g. ketonic carbonyl,
sulfonyl or sulfonyl [other than sulfonamides]) which are generally
susceptible to reduction with this reagent. Suitable conditions are an
excess of zinc dust, e.g., up to a 10-fold molar excess in glacial acetic
acid at about 80.degree.-130.degree. C., conveniently the reflux
temperature of the reaction mixture at ambient pressure, as exemplified
below.
Furthermore, those compounds wherein X is CHOH (carbinol) are also
conveniently prepared by conventional sodium borohydride reduction of the
corresponding compound wherein X is C.dbd.O. In the alternative, compounds
wherein X is CO are also conveniently prepared by oxidation of those
compounds wherein X is CHOH by means of the Jones oxidation.
Those compounds wherein X is SO or SO.sub.2 (with Y as other than NR) or Z
is CH.sub.2 SO or CH.sub.2 SO.sub.2 are preferably formed by suitable
oxidation of the corresponding compounds where X is S or Z is CH.sub.2 S.
When the sulfoxide is desired, the sulfide is preferably oxidized with at
least one molar equivalent (usually a 2-3 fold molar excess) of sodium
periodate in a reaction inert solvent such as aqueous methanol, generally
at room temperature or below so as to avoid over oxidation. Alternatively,
close to one molar equivalent of m-chloroperbenzoic acid can be used for
this purpose, in a reaction-inert solvent such as methylene chloride or
toluene, generally at a reduced temperature such as -10.degree. to
10.degree. C. When the sulfone is desired, a convenient oxidant is at
least two molar equivalents of said m-chloroperbenzoic acid, otherwise in
the same solvents and under the same mild conditions specified in the
preceding sentence. However, a less expensive oxidant for formation of the
sulfone is H.sub.2 O.sub.2 in a reaction inert solvent such as acetic
acid.
When a saturated compound of the formula (I) wherein the dotted line
represents no bond is desired, an alternative synthetic route is to react
thiazolidine-2,4-dione with a compound of the formula
##STR11##
wherein A, B, R, X, X.sup.1, X.sup.2, Y, Z and n are as defined above, and
X.sup.3 is a nucleophilic leaving group such as chloride, bromide, iodide
or mesylate. These reactants are generally used in substantially equimolar
quantities, although 10-25% excess of readily available
thiazolidine-2,4-dione is preferred in order to force the reaction to
completion within a reasonable period of time. The reaction is carried out
in the presence of reaction-inert solvent, such as tetrahydrofuran, with
the thiazolidine-2,4-dione prereacted with two molar equivalents of a
strong base such as butyl lithium in order to preform the dianion. Salt
formation is generally carried out at reduced temperature (e.g.
-50.degree. to -80.degree. C.), the reactants mixed at an intermediate
temperature, and reaction carried to completion at an elevated temperature
(e.g. the reflux temperature of the reaction mixture). It will be evident
to those skilled in the art that this method will be preferred only when
there are no other reactive groups (e.g., unprotected OH or ketonic
carbonyl) present in the compound of the formula (III).
The pharmaceutically-acceptable cationic salts of the compounds of the
present invention are readily prepared by reacting the acid forms with an
appropriate base, usually one equivalent, in a co-solvent. Typical bases
are sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride,
potassium methoxide, magnesium hydroxide, calcium hydroxide, benzathine,
choline, diethanolamine, piperazine and tromethamine. The salt is isolated
by concentration to dryness or by addition of a non-solvent. In many
cases, salts are preferably prepared by mixing a solution of the acid with
a solution of a different salt of the cation (sodium or potassium
ethylhexanoate, magnesium oleate), employing a solvent (e.g., ethyl
acetate) from which the desired cationic salt precipitates, or can be
otherwise isolated by concentration and/or addition of a non-solvent.
The acid addition salts of the compounds of the present invention are
readily prepared by reacting the base forms with the appropriate acid.
When the salt is of a monobasic acid (e.g., the hydrochloride, the
hydrobromide, p-toluenesulfonate, acetate), the hydrogen form of a dibasic
acid (e.g., the hydrogen sulfate, the succinate) or the dihydrogen form of
a tribasic acid (e.g., the dihydrogen phosphate, the citrate), at least
one molar equivalent and usually a molar excess of the acid is employed.
However when such salts as the sulfate, the hemisuccinate, the hydrogen
phosphate or the phosphate are desired, the appropriate and exact chemical
equivalents of acid will generally be used. The free base and the acid are
usually combined in a co-solvent from which the desired salt precipitates,
or can be otherwise isolated by concentration and/or addition of a
non-solvent.
Thiazolidine-2,4-dione is commercially available. The aldehydes and ketones
of formula (II) are prepared by a variety of conventional methods; for
example, by mild oxidation of the corresponding primary or secondary
alcohol with reagents such as manganese dioxide or chromic acid under
conditions known to produce aldehydes from primary alcohols and ketones
from secondary alcohols; reaction of the corresponding aralkyl bromides
with n-butyl lithium followed by N,N-dimethylformamide at -80.degree. to
-70.degree. C. reaction of a suitably 4-substituted benzaldehyde or
acetophenone (or corresponding pyridine analog) with a suitably
substituted benzene derivative so as to form the bridging group:
--(Z).sub.m --(Y).sub.n --X--.
For example:
--CH.sub.2 NH(CH.sub.3)+ClSO.sub.2 --.fwdarw.--CH.sub.2 N(CH.sub.3)SO.sub.2
--
--CH.sub.2 CH.sub.2 SH+Br--.fwdarw.--CH.sub.2 CH.sub.2 --S--
--SH+BrCH.sub.2 CH.sub.2 --.fwdarw.--S--CH.sub.2 CH.sub.2 --
--CH.sub.2 CH.sub.2 NH.sub.2 +ClCO--.fwdarw.--CH.sub.2 CH.sub.2 NHCO--
--CHO+CH.sub.3 CO--.fwdarw.--CH.dbd.CH--CO--
--CH.dbd.CH--CO--.fwdarw.--CH.sub.2 CH.sub.2 --CO--
--CH.dbd.CH--CO--.fwdarw.--CH.sub.2 CH.sub.2 CH.sub.2 --
--CH.sub.2 CH.sub.2 COOH.fwdarw.--CH.sub.2 CH.sub.2 --CO--
The halides/mesylates of the formula (III) are also available by
conventional methods, such as by the action of a suitable reagent (e.g.,
PBr.sub.3, CH.sub.3 SO.sub.2 Cl or the corresponding alcohol),
halogenation of a corresponding methyl derivative, and so forth.
It will be further evident to those skilled in the art that the synthesis
of a compound of the formula (I) can be varied by coupling of a precursor
ketone or aldehyde (or mesylate/halide) with thiazolidine-2,4-dione, with
completion of the side chain as a later step, using one of the synthetic
methods illustrated above for the preparation of ketones and aldehydes of
the formula (II).
The present compounds of the formula (I) are readily adapted to clinical
use as hypoglycemic agents. The activity required for this clinical use is
defined by the test for hypoglycemic effect in ob/ob mice by the following
procedure:
Five to eight week old C57 BL/6J-ob/ob mice (obtained from Jackson
Laboratory, Bar Harbor, Me.) were housed five per cage under standard
animal care practices. After a one week acclimation period, the animals
were weighed and 25 microliters of blood was collected via an ocular bleed
prior to any treatment. The blood sample was immediately diluted 1:5 with
saline containing 2.5 mg/ml sodium fluoride and 2% sodium heparin, and
held on ice for metabolite analysis. Animals were then dosed daily for
five days with drug (5-50 mg/kg), a positive control (50 mg/kg) of
ciglitazone; U.S. Pat. No. 4,467,902; Sohda et al., Chem. Pharm. Bull.,
vol. 32, pp. 4460-4465, 1984), or vehicle. All drugs were administered in
a vehicle consisting of 0.25% w/v methyl cellulose. On day 5, the animals
were weighed again and bled (via the ocular route) for blood metabolite
levels. The freshly collected samples were centrifuged for two minutes at
10,000.times.g at room temperature. The supernatant was analyzed for
glucose, for example, by the ABA 200 Bichromatic Analyzer.TM., using the
A-gent.TM. glucose UV reagent system* (hexokinase method) using 20, 60 and
100 mg/dl standards. Plasma glucose was then calculated by the equation,
Plasma glucose (mg/dl)=Sample value.times.5.times.1.67=8.35.times.Sample
value
where 5 is the dilution factor and 1.67 is the plasma hematocrit adjustment
(assuming the hematocrit is 40%).
.TM.A registered trademark of Abbott Laboratories, Diagnostics Division,
820 Mission Street, So. Pasadena, Calif. 91030.
*A modification of the method of Richterich and Dauwalder, Schweizerische
Medizinische Wochenschrift, 101, 860 (1971).
The animals dosed with vehicle maintain substantially unchanged
hyperglycemic glucose levels (e.g., 250 mg/dl), while positive control
animals have depressed glucose levels (e.g., 130 mg/dl). Test compounds
are reported in terms of % glucose normalization. For example, a glucose
level which is the same as the positive control is reported as 100%.
Studies such as that described below demonstrate that the compounds of
formula (I) also effect the lowering of serum cholesterol levels in
mammals.
Female mice (strain C57Br/cd J), obtained from Jackson Laboratories, Bar
Harbor, Me., are used at age 8-12 weeks, following 2-4 weeks acclimation
having free access to water and standard laboratory chow. Animals are
divided randomly into three groups of 6-7 animals. All three groups are
placed on a diet containing 0.75% cholesterol, 31% sucrose, 15.5% starch,
20% casein, 17% cellulose, 4.5% corn oil, 5% coconut oil, 0.25% cholic
acid, 4% salts and 2% vitamin; permitted to feed ad lib for 18 days; and
dosed daily at 9-11 a.m. for the final 5 days by oral gavage, the control
group with 5 ml/kg of vehicle (0.1% aqueous methyl cellulose) and the test
groups with the compound under study at a dose in the range of 0.1 to 20
mg/kg/day in vehicle. After the fourth day of dosing, the animals are
fasted overnight, starting at 5 p.m. The following morning a fifth and
final dose of the compound is administered to the test groups and, three
hours later, the animals are sacrificed by decapitation. Blood from the
body trunk is collected and allowed to clot, and the serum assayed
enzymatically, using an Abbott VP automated analyzer, for HDL cholesterol,
LDL and VLDL cholesterol, and total cholesterol. Judged on the basis of
LDL+VLDL cholesterol levels, total cholesterol levels or the ratio of
LDL+VLDL/HDL, the compounds of the formula (I) show favorable results in
lowering cholesterol levels.
The present compounds of the formula (I) are clinically administered to
mammals, including man, via either the oral or the parenteral route.
Administration by the oral route is preferred, being more convenient and
avoiding the possible pain and irritation of injection. However, in
circumstances where the patient cannot swallow the medication, or
absorption following oral administration is impaired, as by disease or
other abnormality, it is essential that the drug be administered
parenterally. By either route, the dosage is in the range of about 0.10 to
about 50 mg/kg body weight of the subject per day, preferably about 0.10
to about 10 mg/kg body weight per day administered singly or as a divided
dose. However, the optimum dosage for the individual subject being treated
will be determined by the person responsible for treatment, generally
smaller doses being administered initially and thereafter increments made
to determine the most suitable dosage. This will vary according to the
particular compound employed and with the subject being treated.
The compounds can be used in pharmaceutical preparations containing the
compound, or pharmaceutically-acceptable acid salt thereof, in combination
with a pharmaceutically-acceptable carrier or diluent. Suitable
pharmaceutically-acceptable carriers include inert solid fillers or
diluents and sterile aqueous or organic solutions. The active compound
will be present in such pharmaceutical compositions in amounts sufficient
to provide the desired dosage amount in the range described above. Thus,
for oral administration the compounds can be combined with a suitable
solid or liquid carrier or diluent to form capsules, tablets, powders,
syrups, solutions, suspensions and the like. The pharmaceutical
compositions may, if desired, contain additional components such as
flavorants, sweeteners, excipients and the like. For parenteral
administration the compounds can be combined with sterile aqueous or
organic media to form injectable solutions or suspensions. For example,
solutions in sesame or peanut oil, aqueous propylene glycol and the like
can be used, as well as aqueous solutions of water-soluble
pharmaceutically-acceptable acid addition salts of the compounds. The
injectable solutions prepared in this manner can then be administered
intravenously, intraperitoneally, subcutaneously, or intramuscularly, with
intramuscular administration being preferred in man.
The present invention is illustrated by the following Examples. However, it
should be understood that the invention is not limited to the specific
details of these examples. Nomenclature used herein is based on Rigaudy
and Klesney, IUPAC Nomenclature of Organic Chemistry, 1979 Ed., Pergammon
Press, New York, 1979. The abbreviations THF and DMF refer to
tetrahydrofuran and dimethylformamide, respectively. Jones' Reagent refers
to a solution of chromic anhydride in dilute sulfuric acid (Merck Index,
10th Edition, page ONR-49).
EXAMPLE 1
N-Benzyl-N-methyl-4-[(thiazolidine-2,4-dion-5-yl)methyl]benzenesulfonamide
2,4-Thiazolidinedione (11 mmol, 1.3 g) was dissolved in tetrahydrofuran (50
ml) and cooled to -78.degree. C. N-Butyllithium (22 mmol, 13.8 ml of 1.6M
in hexane) was added over 15 minutes. The cooling bath was removed and the
reaction mixture was stirred for 20 minutes.
N-Benzyl-N-methyl-4-(bromomethyl)benzenesulfonamide (10 mmol, 3.5 g)
dissolved in tetrahydrofuran (50 ml) was added over 20 minutes. The
reaction mixture was heated to reflux for 15 hours, cooled and diluted
with water (50 ml) and 6N HCl (10 ml). The mixture was extracted with
ethyl acetate (75 ml) and the organic layer was dried (Na.sub.2 SO.sub.4)
and removed in vacuo. The residue was purified on silica gel using 1:1
hexane:ethyl acetate to afford 3.0 g of title product as a gum; MS 390
(m.sup.+), 269, 205.
Alternatively, 4-(thiazolidine-2,4-dion-5-yl)benzenesulfonyl chloride (9.6
mmol, 209 g) is dissolved in 100 ml of CH.sub.2 Cl.sub.2 and cooled to
0.degree. C. Benzylmethylamine (20.5 mmol, 2.5 g) dissolved in methylene
chloride (5 ml) is added dropwise and the reaction stirred for minutes.
The solution is washed with 1N HCl (2.times.30 ml), water (2.times.30 ml),
saturated NaCl (2.times.30 ml), dried (Na.sub.2 SO.sub.4) and solvent
removed in vacuo. The residue is purified on silica gel as in the
preceding paragraph to yield the same title product.
EXAMPLE 2
Sodium Salt of
N-Benzyl-N-methyl-4-[(thiazolidine-2,4-dion-5yl)methyl]benzenesulfonamide
The title product of the preceding Example (6.9 mmol, 2.7 g) was dissolved
by warming in 75 ml of ethyl acetate. Sodium 2-ethylhexanoate (6.9 mmol,
1.1 g) in 10 ml ethyl acetate was added. Crystallization of product began
within a few minutes. After standing overnight, present title product was
recovered by filtration, 1.13 g; m.p. 279.degree. C. (dec.), 1.03 g of
which was recrystallized from 20 ml H.sub.2 O to yield 0.44 g purified
title product, m.p. 298.degree. C.
Analysis calculated for C.sub.18 H.sub.17 O.sub.4 N.sub.2 S.sub.2 Na: C,
52.41; H, 4.16; N, 6.79%. Found: C, 52.09; H, 4.11; N, 6.68%.
EXAMPLE 3
N-Methyl-N-(2-phenylethyl)-4-[(thiazolidine-2,4-dion-5-yl)methyl]benzenesul
fonamide
By the method of Example 1,
N-methyl-N-(2-phenylethyl)-4-(bromomethyl)benzenesulfonamide (10.6 mmol,
3.9 g) and thiazolidine-2,4-dione (11.7 mmol 1.4 g,), using 1:2 ethyl
acetate:hexane as eluant, were converted to 3.3 g purified title product
as a gum.
EXAMPLE 4
Sodium Salt of
N-Methyl-N-(2-phenylethyl)-4-[(thiazolidine-2,4-dion-5-yl)methyl]benzenesu
lfonamide
By the method of Example 2, the product of the preceding Example (3.7 mmol,
1.5 g) was converted, without recrystallization, to present title product,
0.74 g; m.p. 279.degree. C. (dec.).
Analysis calculated for C.sub.19 H.sub.19 O.sub.4 N.sub.2 S.sub.2
Na.0.33H.sub.2 O: C, 52.77; H, 4.58; N, 6.48%. Found: C, 52.67; H, 4.52;
N, 6.39%.
EXAMPLE 5
5-[4-(2-Phenylethylthio)phenylmethylene]thiazolidine-2,4-dione
4-(2-Phenylethylthio)benzaldehyde (12.4 mmol, 3.0 g), 2,4-thiazolidinedione
(15.5 mmol, 1.81 g) and anhydrous sodium acetate (30.9 mmol, 2.54 g) were
heated in an oil bath at 150.degree. C. for 0.5 hour. The mixture was
cooled and the resulting solid triturated with water (100 ml) and
collected by filtration. The solid was recrystallized from methanol:ethyl
acetate:acetone (1:1:2) to afford 500 mg of title product; m.p.
182.degree.-183.degree. C.
EXAMPLE 6
Sodium Salt of
5-[4-(2-Phenylethylthio)phenylmethylene]thiazolidine-2,4-dione
By the method of Example 2, the product of the preceding Example (0.15
mmol, 50 mg) was converted to present title product, 40 mg; m.p.
236.degree. C. (dec.).
Analysis calculated for C.sub.18 H.sub.14 O.sub.2 NS.sub.2 Na: C, 59.48; H,
3.88; N, 3.85%.
Found: C, 59.95; H, 4.16; N, 3.79%.
EXAMPLE 7
5-[4-(2-Phenylethylthio)benzyl]thiazolidine-2,4-dione
Title product of Example 5 (4.1 mmol, 1.4 g) and zinc dust (40 mmol, 2.6 g)
were heated to reflux in acetic acid (50 ml) for 15 minutes. The reaction
mixture was filtered and the solvent was removed in vauco. The residue was
purified on silica gel using hexane:ethyl acetate (2:1) plus 5% acetic
acid as eluant to afford 230 mg of present title product; m.p.
58.degree.-65.degree. C.
Analysis calculated for C.sub.18 H.sub.17 NO.sub.2 S.sub.2 : C, 62.97; H,
4.99; N, 4.08%. Found: C, 62.94; H, 5.13; N, 3.91%.
The corresponding sodium salt was prepared according to the method of
Example 2; 215 mg from 230 mg; m.p. greater than 250.degree. C.
EXAMPLE 8
5-[4-(2-Phenylethylsulfinyl)benzyl]thiazolidine-2,4-dione
Title product of the preceding Example (5.8 mmol, 2.0 g) was dissolved in
methanol (125 ml) and added to sodium periodate (17.4 mmol, 3.7 g)
dissolved in water (40 ml) at room temperature. The reaction mixture was
stirred for 1 hour and then concentrated to 50 ml. Water (150 ml) was
added and the solution was extracted with ethyl acetate (2.times.125 ml).
The organic layers were washed with water (50 ml), saturated NaCl (50 ml),
dried (Na.sub.2 SO.sub.4) and solvent removed in vacuo. The residue was
purified on silica gel using hexane:ethyl acetate (1:1) followed by ethyl
acetate as eluant to afford 1.0 g of product which was crystallized from
ethyl acetate:carbon tetrachloride to yield 0.74 g of purified title
product; m.p. 130.degree.-132.degree. C.
Analysis calculated for C.sub.18 H.sub.17 O.sub.3 NS.sub.2 : C, 60.14; H,
4.77; N, 3.90%. Found: C, 60.05; H, 4.77; N, 3.85%.
EXAMPLE 9
Sodium Salt of 5-[4-(2-Phenylethylsulfinyl)benzyl]thiazolidine-2,4-dione
By the method of Example 2, the title product of the preceding Example (3.6
mmol, 1.3 g) was converted, without recrystallization, to 1.14 g of
present title product; m.p. 205.degree. C. (dec.).
Analysis calculated for C.sub.18 H.sub.16 O.sub.3 NS.sub.2 Na: C, 56.67; H,
4.23; N, 3.67%. Found: C, 56.40; H, 4.25; N, 3.61%.
EXAMPLE 10
Sodium Salt of
5-[4-(2-Phenylethylsulfonyl)phenylmethylene]thiazolidine-2,4-dione
m-Chloroperbenzoic acid (11.6 mmol, 2.5 g, 80%) was suspended in methylene
chloride (75 ml) and cooled to 0.degree. C. Title product of Example 5
(5.27 mmol, 1.8 g) was added and the reaction mixture stirred for 1 hour.
Aqueous sodium sulfite was added and the solid was collected by
filtration. Recrystallization from ethyl acetate afforded 0.44 g of the
free acid form of present title product; m.p. 225.degree.-226.degree. C.
The free acid (0.13 mmol, 50 mg) was converted to 38 mg of the title
sodium salt according to the method of Example 2, without
recrystallization; m.p. 265.degree. C. (dec.).
Analysis calculated for C.sub.18 H.sub.14 O.sub.4 N.sub.2 S.sub.2 Na: C,
54.67; H, 3.57; N, 3.54%. Found: C, 54.69; H, 3.92; N, 3.46%.
EXAMPLE 11
5-[4-(2-Phenylethylsulfonyl)benzyl]thiazolidine-2,4-dione
Free acid form of the product of the preceding Example (1.34 mmol, 500 mg)
was hydrogenated in a Paar shaker using 10% Pd/C sulfur resistant catalyst
(300 mg) at 50 psig for 18 hours at room temperature in THF (50 ml). The
catalyst was removed by filtration, the solvent removed in vacuo, and the
residue recrystallized from ethyl acetate to afford present title product,
400 mg; m.p. 201.degree.-203.degree. C.
Analysis calculated for C.sub.18 H.sub.17 NO.sub.4 S.sub.2 : C, 57.58; H,
4.57; N, 3.73%. Found: C, 57.82; H, 4.64; N, 3.71%.
EXAMPLE 12
Sodium Salt of 5-[4-(2-Phenylethylsulfonyl)benzyl]thiazolidine-2,4-dione
By the method of Example 2, without recrystallization, the product of the
preceding Example (1.33 mmol, 500 mg) was converted to 380 mg of present
title product; m.p. 288.degree. C. (dec.).
Analysis calculated for C.sub.18 H.sub.16 O.sub.4 NS.sub.2 Na: C, 54.39; H,
4.06; N, 3.52%. Found: C, 53.53; H, 4.19; N, 3.36%.
EXAMPLE 13
5-[1-(4-(2-Phenylethylthio)phenyl)ethylidene]thiazolidine-2,4-dione
4-(2-Phenylethylthio)acetophenone (30 mmol, 7.7 g), 2,4-thiazolidinedione
(30 mmol, 3.5 g) and sodium acetate (60 mmol, 4.9 g) were fused in an oil
bath at 190.degree. C. for 0.5 hour. The solid was cooled and dissolved in
water (50 ml) and ethyl acetate (50 ml). The layers were separated and the
ethyl acetate washed with water (2.times.50 ml), dried (Na.sub.2 SO.sub.4)
and stripped in vacuo. The residue was crystallized from ether to afford
1.7 g of title product; m.p. 183.degree.-187.degree. C.
Analysis calculated for C.sub.19 H.sub.17 O.sub.2 NS.sub.2 : C, 64.19; H,
4.82; N, 3.94%. Found: C, 64.73; H, 4.81; N, 3.36%.
The corresponding sodium salt was prepared according to the method of
Example 2.
EXAMPLE 14
5-[1-(4-(2-Phenylethylthio)phenyl)ethyl]thiazolidine-2,4-dione
By the method of Example 7, the title product of the previous Example was
converted to present chromatographically purified title product as an oil.
Analysis calculated for C.sub.19 H.sub.19 O.sub.2 NS.sub.2 : C, 63,86; H,
5.36; N, 3.92%. Found: C, 63.67; H, 5,42; N, 3.94%.
The corresponding sodium salt was prepared according to the method of
Example 2, without recrystallization; m.p. 260.degree.-265.degree. C.
EXAMPLE 15
5-[1-(4-(2-Phenylethylsulfonyl)phenyl)ethyl]thiazolidine-2,4-dione
Title product of the preceding Example (1 mmol, 360 mg) was dissolved in
acetic acid (20 ml) at room temperature. 30% Hydrogen peroxide (5 ml) was
added and the mixture stirred for 18 hours. The solution was diluted with
water (75 ml) and stirred for 2 hours to afford a gummy precipitate. The
liquid was decanted and the residue triturated with water (10 ml) and
hexane (10 ml) to afford 200 mg of present title product as a white solid;
m.p. 135.degree.-145.degree. C.
Analysis calculated for C.sub.19 H.sub.19 O.sub.4 NS.sub.2 : C, 58.61; H,
4.92; N, 3.60%. Found: C, 58.86; H, 4.95; N, 3.55%.
The corresponding sodium salt was prepared according to the method of
Example 2.
EXAMPLE 16
5-[1-(4-(2-Phenylethylsulfonyl)phenyl)ethylidene[thiazolidine-2,4-dione
Title product of Example 13 (1.41 mmol, 500 mg) was added to a solution of
m-chloroperbenzoic acid (3.10 mml, 535 mg) slurried in methylene chloride
(15 ml) at 0.degree. C. The reaction mixture was stirred for 1 hour at
room temperature. The mixture was diluted with CHCl.sub.3 (60 ml), washed
with 10% Na.sub.2 SO.sub.3 (20 ml), saturated NaHCO.sub.3 (2.times.20 ml)
and saturated NaCl (20 ml), dried (Na.sub.2 SO.sub.4), and solvent removed
in vacuo. The crude solid was recrystallized from acetic acid to afford
present title product as yellow crystals; m.p. 201.degree.-202.degree. C.
Analysis calculated for C.sub.19 H.sub.17 O.sub.4 NS.sub.2 : C, 58.89; H,
4.42; N, 3.62%. Found: C, 58.65; H, 4.63; N, 3.46%.
The corresponding sodium salt was prepared, without recrystallization,
according to the method of Example 2; m.p. 269.degree. C. (dec.).
EXAMPLE 17
5-[4-(2-(4-Chlorophenyl)ethylthio)phenylmethylene]thiazolidine-2,4-dione
4-[2-(4-Chlorophenyl)ethylthio]benzaldehyde and thiazolidine-2,4-dione were
coupled according to the method of Example 5 to form present title product
in similar yield; m.p. 215.degree.-225.degree. C.
Analysis calculated for C.sub.18 H.sub.14 ClNO.sub.2 S.sub.2 : C, 57.51; H,
3.76; N, 3.73%. Found: C, 57.27; H, 3.77; N, 3.59%.
EXAMPLE 18
Sodium Salt of
5-[4-(2-(4-Chlorophenyl)ethylthio)phenylmethylene]thiazolidine-2,4-dione
By the method of Example 2, without recrystallization, the title product of
the preceding Example was converted to present title product in similar
yield; m.p. greater than 240.degree. C.
Analysis calculated for C.sub.18 H.sub.13 ClNO.sub.2 S.sub.2 Na: C, 54.33;
H, 3.29; N, 3.52%. Found: C, 54.34; H, 3.45; N, 3.31%.
EXAMPLE 19
Sodium Salt of
5-[4-(2-(4-Chlorophenyl)ethylthio)benzl]thiazolidine-2,4-dione
By the method of Example 7, the title product of Example 17 (9.84 mmol, 3.7
g) was reduced to present title product, chromatographed on silica gel
using 4:1 hexane:ethyl acetate as eluant, initially isolating the free
acid form of title product as an oil (1.3 g) which solidified on pumping
under vacuum; m.p. 100.degree. C.
The free acid was converted to title sodium salt by dissolving the free
acid (2.14 mmol, 0.875 g) in 10 ml CH.sub.3 OH and 10 ml of ethyl acetate
with warming, adding 2.14 ml of 1M NaOC.sub.2 H.sub.5 in ethanol (2.14
mmol), stirring 30 minutes, stripping away solvent and triturating the
residue with ether to yield 0.8 g of title product; m.p. greater than
250.degree. C.
Analysis calculated for C18H15ClNO.sub.2 S.sub.2 Ha: C, 54.06; H, 3.78; N,
3.50%. Found: C, 53.79; H, 3.76; N, 3.39%.
EXAMPLE 20
5-[4-(2-(4-Chlorophenyl)ethylsulfonyl)phenylmethylene]thiazolidine-2,4-dion
e
By the method of Example 10, the title product of Example 17 (23.2 mmol, 5
g) was oxidized to 2.4 g of present title product following
recrystallization from ethyl acetate; m.p. 242.degree.-243.degree. C.
Free acid (1.3 g) was converted to 1.36 g of the corresponding sodium salt
by the method used in the preceding Example; m.p. greater than 250.degree.
C.
EXAMPLE 21
Sodium Salt of
5-[4-(2-(4-Chlorophenyl)ethylsulfonyl)benzyl]thiazolidine-2,4-dione
By the method of Example 11, the title product of the preceding Example
(1.7 g) was hydrogenated to produce present title product, purified by
chromatography on silica gel using gradient elution with 4:1, 3:1 and
finally 2:1 hexane:ethyl acetate to yield 0.93 g of the purified free acid
form title product as a white solid; m.p. 168.degree.-171.degree. C.
The latter (0.9 g) was converted to 0.85 g of the sodium salt according to
the method of Example 19; m.p. greater than 250.degree. C.
Analysis calculated for C.sub.18 H.sub.15 ClNO.sub.4 S.sub.2 Na: C, 54.06;
H, 3.78; N, 3.50%. Found: C, 53.79; H, 3.76; N, 3.39%.
EXAMPLE 22
5-[4-(Benzylthio)phenylmethylene]thiazolidine-2,4-dione
4-(Benzylthio)benzaldehyde (20.8 g) was fused with thiazolidine-2,4-dione
according to the method of Example 5 to afford 15 g of present title
product; m.p. 237.degree.-238.degree. C.
EXAMPLE 23
Sodium Salt of 5-[4-(Benzylthio)phenylmethylene]thiazolidine-2,4-dione
By the method of Example 2, without recrystallization, the title product of
the preceding Example was converted to present title product in similar
yield; m.p. greater than 250.degree. C.
EXAMPLE 24
5-[4-(Benzylthio)benzyl]thiazolidine-2,4-dione
By the method of Example 7, the title product of Example 22 (1.31 g) gave,
after recrystallization from ether:hexane, 0.35 g of present title
product; m.p. 102.degree.-103.degree. C.
Analysis calculated for C.sub.17 H.sub.15 NO.sub.2 S.sub.2 : C, 61.97; H,
4.59; N, 4.25%. Found: C, 62.24; H, 4.51; N, 4.16%.
The corresponding sodium salt was prepared according to Example 2; m.p.
greater than 250.degree. C.
EXAMPLE 25
Sodium Salt of 5-[4-(Benzylsulfonyl) benzyl]thiazolidine-2,4-dione
By the method of Example 10, the title product of the preceding Example
(2.0 g) was converted, after recrystallization from ethyl acetate, to 1.14
g of the free acid form of present title product; m.p. 175.degree. C.
The sodium salt was prepared according to Example 19 in similar yield; m.p.
greater than 250.degree. C.
Analysis calculated for C.sub.17 H.sub.14 NO.sub.4 S.sub.2 Na: C, 53.25; H,
3.68; N, 3.65%. Found: C, 55.36; H, 3.74; N, 3.58%.
EXAMPLE 26
5-[4-(3-Phenylpropylthio)phenylmethylene]thiazolidine-2,4-dione
By the method of Example 5, 4-(3-phenylpropylthio)benzaldehyde (7.0 mmol,
1.8 g) gave 1.8 g of title product, recrystallized from acetic acid; m.p.
172.degree.-173.degree. C.
Analysis calculated for C.sub.19 H.sub.17 O.sub.2 NS.sub.2 : C, 64.19; H,
4.82; N, 3.94%. Found: C, 64.18; H, 4.75; N, 3.76%.
EXAMPLE 27
Sodium Salt of
5-[4-(3-Phenylpropylthio)phenylmethylene]thiazolidine-2,4-dione
By the method of Example 2, without recrystallization, title product of the
preceding Example (1.0 g) was converted to 0.98 g of present title
product; m.p. 240.degree.-275.degree. C. (dec.).
EXAMPLE 28
5-[4-(3-Phenylpropylthio)benzyl]thiazolidine-2,4-dione
By the method of Example 7, the title product of Example 26 (1.8 g) was
reduced to 0.49 g of present title product, recrystallized from 1:1
hexane:isopropyl ether; m.p. 88.degree.-89.degree. C.
Analysis calculated for C.sub.19 H.sub.19 O.sub.2 NS.sub.2 : C, 63.83; H,
5.36; N, 3.92%. Found: C, 64.27; H, 5.43; N, 3.87%.
EXAMPLE 29
Sodium Salt of 5-[4-(3-Phenylpropylthio)benzyl]thiazolidine-2,4-dione
By the method of Example 2, without recrystallization, the title product of
the preceding Example (1.5 g) was converted to 1.09 g of present title
product; m.p. 286.degree. C. (dec.).
EXAMPLE 30
Sodium Salt of 5-[4-(3-Phenylpropylsulfinyl)benzyl]thiazolidine-2,4-dione
By the method of Example 8, the title product of Example 28 (3.9 mmol, 1.4
g) was converted to 1.2 g of chromatographed free acid form title product
as a gum; tlc Rf 0.3 (ethyl acetate). The latter was converted to 1.29 g
of sodium salt according to the method of Example 2 (without
recrystallization); m.p. 210.degree. C. (dec.).
Analysis calculated for C.sub.19 H.sub.18 O.sub.3 NS.sub.2 Na: C, 57.70; H,
4.59; N, 3.54%. Found: C, 57.31; H, 4.57; N, 3.42%.
EXAMPLE 31
5-[4-(3-Phenylpropylsulfonyl)phenylmethylene]thiazolidine-2,4-dione
By the method of Example 10, the title product of Example 26 (4.0 mmol,
1.42 g) was converted to 1.1 g of present title product recrystallized
from acetic acid; m.p. 224.degree.-225.degree. C.
Analysis calculated for C.sub.19 H.sub.17 O.sub.4 NS.sub.2 : C, 58.89; H,
4.42; N, 3.62%. Found: C, 59.16; H, 4.24; N, 3.55%.
EXAMPLE 32
Sodium Salt of
5-[4-(3-Phenylpropylsulfonyl)phenylmethylene]thiazolidine-2,4-dione
By the method of Example 2, without recrystallization, title product of the
preceding Example (1.22 g) was converted to 1.19 g of present title
product; m.p. 255.degree. C. (dec.).
EXAMPLE 33
5-[4-(3-Phenylpropylsulfonylbenzyl]thiazolidine-2,4-dione
By the method of Example 11, the title product of Example 31 (1.0 g) was
converted to 0.85 g of present title product purified by silica gel
chromatography using 1:1 hexane:ethyl acetate as eluant, initially
isolated as an oil which crystallized on standing; m.p.
126.degree.-127.degree. C.
Analysis calculated for C.sub.19 H.sub.19 O.sub.4 NS.sub.2 : C, 58.59; H,
4.92; N, 3.60%. Found: C, 58.86; H, 5.00; N, 3.54%.
EXAMPLE 34
Sodium Salt of 5-[4-(3-Phenylpropylsulfonyl)benzyl]thiazolidine-2,4-dione
By the method of Example 2, without recrystallization, the title product of
the preceding Example (1.54 mmol, 0.60 g) was converted to 0.52 g of
present title product; m.p. 288.degree. C. (dec.).
Analysis calculated for C.sub.19 H.sub.18 O.sub.4 NS.sub.2 Na: C, 55.46; H,
4.41; N, 3.40%. Found: C, 55.53; H, 4.38; N, 3.13%.
EXAMPLE 35
5-[4-(2-(Phenylthio)ethyl)phenylmethylene]thiazolidine-2,4-dione
By the method of Example 5, 4-[2-(phenylthio)ethyl]benzaldehyde (26 mmol,
6.3 g) was converted to 6.0 g of present title product following
recrystallization from acetic acid; m.p. 159.degree.-161.degree. C.
Analysis calculated for C.sub.18 H.sub.15 O.sub.2 NS.sub.2 : C, 63.31; H,
4.43; N, 4.10%. Found: C, 63.25; H, 4.37; N, 4.02%.
EXAMPLE 36
Sodium Salt of
5-[4-(2-(Phenylthio)ethyl)phenylmethylene]thiazolidine-2,4-dione
By the method of Example 2, without recrystallization, the title product of
the preceding Example (1.54 mmol, 0.525 g) was converted to 0.50 g of
present title product; m.p. 270.degree. C. (dec.).
Analysis calculated for C.sub.18 H.sub.14 O.sub.2 NS.sub.2 Na: C, 59.48; H,
3.88; N, 3.85%. Found: C, 59.24; H, 3.85; N, 3.72%.
EXAMPLE 37
Sodium Salt of 5-[4-(2-(Phenylthio)ethyl)benzyl]thiazolidine-2,4-dione
By the method of Example 7, title product of Example 35 (2.9 mmol, 1.0 g)
was converted to 0.26 g of the purified free acid form of present title
product, isolated from the chromatography as a gum.
Analysis calculated for C.sub.18 H.sub.17 O.sub.2 NS.sub.2 : C, 62.94; H,
4.99; N, 4.08%. Found: C, 62.73; H, 5.01; N, 3.95%.
The free acid (1.76 g) was converted to 1.2 g of the corresponding sodium
salt by the method of Example 2 (without recrystallization); m.p.
290.degree. C. (dec.).
Analysis calculated for C.sub.18 H.sub.16 O.sub.2 NS.sub.2 Ha: C, 59.15; H,
4.41; N, 3.83%. Found: C, 58.77; H, 4.37; N, 3.78%.
EXAMPLE 38
Sodium Salt of 5-[4-(2-(Phenylsulfonyl)ethyl)benzyl]thiazolidine-2,4-dione
By the method of Example 10, the free acid form of the title product of the
preceding Example (4.1 mmol, 1.4 g) was converted to 0.70 g of the free
acid form of present title product, isolated as a gum from chromatography
on silica gel using 1:1 hexane:ethyl acetate as eluant.
Analysis calculated for C.sub.18 H.sub.17 O.sub.4 NS.sub.2 : C, 57.58; H,
4.56; N, 3.73%. Found: C, 57.96; H, 4.70; N, 3.49%.
The sodium salt was formed according to the method of Example 2; m.p.
285.degree. C. (dec.).
Analysis calculated for C.sub.18 H.sub.16 O.sub.4 NS.sub.2 Na: C, 54.39; H,
4.06; N, 3.52%. Found: C, 54.11; H, 4.20; N, 3.40%.
EXAMPLE 39
(E)-5-[4-(3-Phenyl-2-propenoyl)benzyl]thiazolidine-2,4-dione
To a slurry of 5-(4-acetylbenzyl)thiazolidine-2,4-dione (4.0 mmol, 1.0 g),
and benzaldehyde (4.0 mmol, 0.41 ml) in ethanol (10 ml) was added sodium
methoxide (4.8 mmol, 260 mg). The solution was heated to reflux for 1.5
hours, then more benzaldehyde was added and the mixture was heated another
1.5 hours, then cooled, diluted with water (60 ml), acidified with 2N HCl
and extracted with ethyl acetate (2.times.50 ml). The combined extracts
were washed with water (50 ml), dried over sodium sulfate and concentrated
in vacuo. The residue was recrystallized from isopropanol to give title
product as a pale yellow solid (0.33 g, 24%); m.p. 147.degree.-149.degree.
C.
Analysis calculated for C.sub.19 H.sub.15 NO.sub.3 S: C, 67.63; H, 4.48; N,
4.15%. Found: C, 67.40; H, 4.57; N, 4.00%.
EXAMPLES 40-52
(E)-5-[4-(3-(Substituted-phenyl)-2-propenopyl)benzyl]thiazolidine-2,4-dione
Substituting a molar equivalent of the appropriately substituted
benzaldehyde for benzaldehyde in the process of Example 39 gave the
following additional compounds:
__________________________________________________________________________
HRMS.sup.i
Phenyl Rx.sup.a or Ch.sup.a
Yield
Calcd.
No. Substit..sup.f
Solvent.sup.f
(%) (Found)
m.p. (.degree.C.)
__________________________________________________________________________
40 2-OCH.sub.3
None 81 367.0915
88-9
(367.0878)
(dec.)
41 2-Cl Rx HOAc 52 -- 193-6
42.sup.b
2-CF.sub.3
Ch CHCl.sub.3 :CH.sub.3 OH
22 405.0684
251-4.sup.c
20:1 (405.0646)
43.sup.d
2-CH.sub.2 Ph
None 32 -- 235-8.sup.c
44.sup.d
2-OCH.sub.2 OMe
Ch hexane:EtOAc
36 -- 285
1:1 (dec.)
45.sup.d
2-CH.sub.3
None 5 -- 250.sup.c
(dec.)
46 4-OCH.sub.2 Ph
Rx Me.sub.2 CHOH
73 443.1194
240
(443.1192)
(dec.)
47.sup.d
4-Br None .sup. 45.sup.e
-- above
300.degree. C.
48.sup.d
4-Ph None 60 413.1099
above
(413.1086)
300.degree. C.
49 4-NO.sub.2
None 68 382.0578
245.sup.c
(382.0623)
(dec.)
50 3-Cl None 41 -- 264-6.sup.c
51.sup.b
3-NO.sub.2
Ch hexane:EtOAc
52 -- 265.sup.g
1:1
52.sup.h
4-OCH.sub.2 OMe
Ch 3% CH.sub.3 OH
36 -- 285.sup.c
in CHCl.sub.3
__________________________________________________________________________
.sup.a Rx = recrystallization; Ch = chromatography.
.sup.b Dimethylsulfoxide used in place of ethanol.
.sup.c As the sodium salt, obtained by combining 360 mg of free acid with
a molar equivalent of NaOCH.sub.3 in 10 ml CH.sub.3 OH, and evaporation.
.sup.d KOC(CH.sub.3).sub.3 used in place of NaOCH.sub.3.
.sup.e Initially isolated as the potassium salt in 82% yield.
.sup.f Ph = phenyl; Me = methyl; HOAc = acetic acid; EtOAc = ethyl
acetate.
.sup.g As the sodium salt, 395 mg obtained according to the method of
Example 2 from 500 mg of free acid; Analysis calculated for C.sub.19
H.sub.13 N.sub.2 O.sub.5 SNa: C, 56.43; H, 3.24; N, 6.93%.
Found: C, 56.27; H, 3.02; N, 6.27%.
.sup.h NaOH in place of NaOCH.sub.3 and 1:1 H.sub.2 O:CH.sub.3 OH in plac
of ethanol.
.sup.i HRMS = High Resolution Mass Spectroscopy.
EXAMPLE 53
(E)-5-[4-(3-(2-Hydroxyphenyl)-2-propenoyl)benzyl]thiazolidine-2,4-dione
The product of Example 44 (310 mg, 0.78 mmol) was dissolved in THF (5 ml)
and 3M sulfuric acid (3 ml). After 2 hours the solution was diluted with
water (75 ml) and extracted with ethyl acetate (2.times.75 ml). The
combined extracts were washed with water (2.times.50 ml), brine (50 ml),
dried over sodium sulfate and concentrated in vacuo, leaving present title
product as a yellow gummy foam (247 mg, 90%).
The sodium salt was prepared as described for Example 42 and obtained as an
orange solid; m.p. 108.degree. C. (dec.).
Analysis calculated for C.sub.19 H.sub.14 NO.sub.3 SNa.1/2H.sub.2 O: C,
59.36; H, 3.93; N, 3.64%. Found: C, 59.07; H, 4.12; N, 3.43%.
By the same method, the product of Example 52 is converted to
(E)-5-[4-(3-(4-hydroxyphenyl)-2-propenoyl)benzyl]thiazolidine-2,4-dione.
EXAMPLE 54
(E)-5-[4-(3-(2-Methanesulfonyloxyphenyl)-2-propenoyl)benzyl]thiazolidine-2,
4-dione
To a solution of the title product of the preceding Example (246 mg, 0.70
mol) in dichloromethane (10 ml) was added triethylamine (0.12 ml, 0.84
mmol), followed by methanesulfonyl chloride (0.070 ml, 0.84 mmol). The
solution was stirred for 3 hours at room temperature, then diluted with
dichloromethane (40 ml) and washed with water (25 ml), saturated aqueous
sodium bicarbonate (2.times.25 ml), water (25 ml) and brine (25 ml), dried
over sodium sulfate and concentrated in vacuo. After flash-chromatography
(hexane:ethyl acetate 1:2) present title product was obtained as a yellow
solid (82 mg, 27%).
HRMS (C.sub.20 H.sub.17 NO.sub.6 S.sub.2). Calc.: 352.0643. Found 352.0667.
The sodium salt was prepared as described for Example 42 and obtained as a
yellow solid; m.p. 198.degree.-200.degree. C.
EXAMPLE 55
(E)-5-[4-(3-(4-Methoxyphenyl)-2-propenoyl)benzyl]thiazolidine-2,4-dione
Hydrogen chloride was bubbled into an ice-cooled solution of
5-(4-acetylbenzyl)thiazolidine-2,4-dione (1.0 g, 4.0 mmol) and
p-anisaldehyde (0.55 g, 4.0 mol) in ethanol (15 ml) for 1 hour. The
solution was stirred overnight at room temperature, then diluted with
water and the yellow precipitate of present title product collected and
dried (1.37 g, 93%); m.p. 177.degree.-180.degree. C.
HRMS (C.sub.20 H.sub.16 NO.sub.4 S M-H.sup.+). Calc.: 366.0800. Found:
366.0939.
The sodium salt was prepared as described in Example 42; m.p.
275.degree.-280.degree. C.
EXAMPLE 56
(E)-5-[4-(3-(4-Acetylaminophenyl)-2-propenoyl)benzyl]thiazolidine-2,4-dione
By the method of the preceding Example, 4-acetylaminobenzaldehyde (0.65 g,
4.0 mmol) was converted to present title product (1.36 g, 86%).
HRMS (C.sub.21 H.sub.18 N.sub.2 O.sub.4 S). Calc.: 394.0988. Found:
394.1009.
The sodium salt was prepared as described in Example 42; m.p. 250.degree.
C. (dec.).
EXAMPLE 57
5-[4-(3-Phenylpropionyl)benzyl]thiazolidine-2,4-dione
To an ice-cooled solution of the title product of Example 39 (2.0 g, 5.9
mmol) in trifluoroacetic acid (20 ml) was added triethylsilane (0.95 ml,
5.9 mmol). The mixture was stirred for 25 minutes at 0.degree. C., then
diluted with water (50 ml) and extracted with ether (2.times.40 ml). The
combined extracts were washed with water (2.times.40 ml) and 5% sodium
bicarbonate (2.times.40 ml), dried over sodium sulfate and concentrated in
vacuo. The residue was triturated with hexane to give present title
product as a pale yellow solid (1.65 g, 82%); m.p. 119.degree.-121.degree.
C.
The sodium salt was prepared as described in Example 42; m.p. greater than
230.degree. C.
EXAMPLES 58-61
5-[4-(3-Substituted-phenyl)propionyl)benzylthiazolidine-2,4-dione
Substituting the appropriate
5-[4-(3-(substituted-phenyl)-2-propenoyl)benzyl]thiazolidine-2,4-dione for
the title product of Example 39 in the preceding Example gave the
following additional compounds:
______________________________________
HRMS
Phenyl Chromatog. Yield Calcd. m.p.
No. Substit. Solvent (%) (Found) (.degree.C.)
______________________________________
58 2-OCH.sub.3
None 72 -- 269
(dec.).sup.a,b
59 4-CH.sub.2 Ph
5% CH.sub.3 OH
77 445.1367
97-101
in CHCl.sub.3 (445.1347)
60 4-Ph 5% CH.sub.3 OH
55 415.1230
270.sup.a
in CHCl.sub.3 (415.1242)
61 4-OCH.sub.3
hexane:ETOAc
36 -- 272-4.sup.a
2:3
______________________________________
.sup.a As the sodium salt
.sup.b Analysis calculated for C.sub.20 H.sub.18 NO.sub.4 SNa: C, 61.37;
H, 4.63; N, 3.58%.
Found: C, 61.15; H, 4.63; N, 3.53%.
EXAMPLE 62
5-[4-(3-(3-Methoxyphenylpropionyl)benzyl]thiazolidine-2,4-dione
3-[4-[3-(3-Methoxyphenyl)propionyl]phenyl]-2-bromopropionic acid (0.73 mg,
1.9 mmol) and thiourea (0.28 g, 3.7 mmol) were dissolved in sulfolane (1
ml) and heated to 105.degree.-110.degree. C. for 5 hours. 2N HCl (1 ml)
was then added and the solution was heated to 105.degree.-110.degree. C.
overnight. The mixture was cooled, diluted with water (30 ml) and
extracted with ethyl acetate (2.times.30 ml). The combined extracts were
washed with water (4.times.30 ml) and brine (40 ml), dried over sodium
sulfate and concentrated in vacuo. The product was purified by
flash-chromatography (hexane:ethyl acetate, 1:1), to give present title
product as a gummy solid.
The sodium salt was prepared as described in Example 2; m.p. 274.degree. C.
(dec.).
EXAMPLE 63
5-[4-(1-Hydroxy-3-phenylpropyl)benzyl]thiazolidine-2,4-dione
To an ice-cooled solution of title product of Example 57 (1.65 g, 4.9 mmol)
in methanol (35 ml) was added sodium borohydride (185 mg, 4.9 mmol). The
solution was stirred for 2 hours at room temperature, then quenched with
1N HCl, diluted with water (100 ml) and extracted with ethyl acetate
(3.times.50 ml). The combined extracts were washed with water (50 ml) and
brine (50 ml), dried over sodium sulfate and concentrated in vacuo,
leaving present title product as an oil (1.61 g, 97%).
The sodium salt was prepared in 77% yield as described in Example 42; m.p.
249.degree.-254.degree. C.
EXAMPLE 64
5-[4-(3-Phenylpropyl)benzyl]thiazolidine-2,4-dione
A solution of the title product of Example 39 (2.0 g, 5.9 mmol) in
trifluoroacetic acid (20 ml), cooled to 0.degree. C., was treated with
triethylsilane (2.8 ml, 18 mmol). After 25 minutes at 0.degree. C., the
solution was diluted with water (60 ml) and extracted with ether
(2.times.50 ml). The combined extracts were washed with water (2.times.50
ml) and brine (50 ml), dried over sodium sulfate and concentrated in
vacuo, leaving a brown oil. Present title product was isolated by
flash-chromatography (hexane:ethyl acetate, 5:1) as an oil (1.11 g, 58%).
The sodium salt was prepared as described in Example 42; m.p. 286.degree.
C.
EXAMPLE 65
5-[4-(3-Phenyl-2,3-epoxypropionyl)benzyl]thiazolidine-2,4-dione
To a solution of title product of Example 39 (0.5 g, 1.5 mmol) in methanol
(4 ml), cooled to 0.degree. C., was added 30% H.sub.2 O.sub.2 (0.5 ml, 4.8
mmol), followed by 2N NaOH (1.6 ml, 3.2 mmol). After 30 minutes at
0.degree. C. the solution was acidified with 2N HCl, diluted with water
(15 ml) and extracted with ethyl acetate (2.times.15 ml). The combined
extracts were washed with brine (15 ml), dried over magnesium sulfate and
concentrated in vacuo, leaving present title product as an oil (420 mg,
80%). HRMS (C.sub.19 H.sub.15 NO.sub.4 S). Calc.: 353.0721. Found:
353.0755.
The sodium salt was prepared as described in Example 42; m.p.
207.degree.-209.degree. C.
EXAMPLE 66
5-[4-(4-Phenylbutyryl)phenylmethylene]thiazolidine-2,4-dione
An intimate mixture of the title product of Preparation 20 (2.35 g, 9.3
mmol), sodium acetate (2.29 g, 27.9 mmol) and 2,4-thiazolidinedione (1.64
g, 1.4 mmol) was heated to 150.degree. C. for 30 minutes. After cooling,
the contents of the flask were cooled, pulverized and washed with water
(50 ml) and then 5% methanol in ether (40 ml). The product was dried to
afford 2.92 g (93%) of present title product as a yellow solid; m.p.
greater than 280.degree. C.
EXAMPLE 67
5-[(2-(3-Phenylpropionyl)-5-pyridyl)methylene]thiazolidine-2,4-dione
By the method of the preceding Example, title product of Preparation 21 was
converted to present title product in 96% yield; m.p. greater than
250.degree. C.
EXAMPLE 68
5-[(5-(3-Phenylpropionyl)-2-pyridyl)methylene]thiazolidine-2,4-dione
By the method of Example 66, title product of Preparation 22 was converted
to present title product in quantitative yield; m.p. greater than
250.degree. C.
EXAMPLE 69
Sodium Salt of 5-[4-(4-Phenyl-1-hydroxybutyl)benzyl]thiazolidine-2,4-dione
To the title product of Example 66 (2.80 g, 8.3 mmol) in methanol (100 ml)
was added 3% sodium amalgam (100 g) and the reaction mixture was stirred
for 4 hours at ambient temperature. The organic solution was then
decanted, concentrated, diluted with water (100 ml) and acidified to pH 2
with 2N HCl. The aqueous was extracted with CH.sub.2 Cl.sub.2 (3.times.50
ml), dried and concentrated to give 796 mg of a colorless oil.
Purification via radial chromatography (2% CH.sub.3 OH in CH.sub.2
Cl.sub.2) gave the free acid form of present title product (178 mg, 6%)
isolated as an oil.
To a solution of the latter (85 mg, 0.25 mmol) in a small amount of
methanol was added sodium methoxide (15 mg, 0.28 mmol). The reaction was
concentrated to dryness and triturated with 1:10 CH.sub.3 OH:ether (5 ml)
and then filtered to afford 27 mg (29%) of present title product; m.p.
244.degree.-246.degree. C.
EXAMPLE 70
5-[(2-(3-Phenyl-1-hydroxypropyl)-5-pyridyl)methyl]thiazolidine-2,4-dione
To a solution of the title product of Example 67 (260 mg, 0.77 mmol) in
methanol (10 ml) was added 3% sodium amalgam (4 g) and the reaction was
stirred for 4 hours. The methanol was decanted, evaporated and the
resultant solid diluted with water (10 ml). The aqueous solution was
adjusted to pH 2 with 1N HCl and extracted with CH.sub.2 Cl.sub.2
(3.times.10 ml) which was discarded. After neutralization of the aqueous
layer to pH 7 with NaHCO.sub.3, it was then re-extracted with CH.sub.2
Cl.sub.2 (3.times.10 ml). These combined organic layers were dried
(MgSO.sub.4), filtered and concentrated to afford the desired product (94
mg, 36%) isolated as a foam.
EXAMPLE 71
5-[(5-(3-Phenyl-1-hydroxypropyl)-2-pyridyl)methyl]thiazolidine-2,4-dione
By the method of Example 69, the title product of Example 68 was converted
to present chromatographed title product as an oil in 34% yield.
EXAMPLE 72
Sodium Salt of
5-[(5-(3-Phenyl-1-hydroxypropyl)-2-pyridyl)methyl]thiazolidine-2,4-dione
To a solution of title product of the preceding Example (70 mg, 0.20 mmol)
in ethyl acetate (1 ml) was added sodium 2-ethylhexanoate (32 mg, 0.19
mmol) and ether (1 ml). After stirring for 1 hour, the white solid was
collected via vacuum filtration and dried to give the expected product (43
mg, 60%) isolated as a white solid; m.p. 251.degree. C. (dec.).
EXAMPLE 73
5-[4-(4-Phenylbutyryl)benzyl]thiazolidine-2,4-dione
To a solution of the title product of Example 66 (145 mg, 0.408 mmol) in
acetone (10 ml) at 0.degree. C. was added in a dropwise fashion Jones'
Reagent (2.67M, 0.39 ml, 1.0 mmol). After stirring for 2 hours at room
temperature, the reaction was quenched by the addition of isopropanol (1
ml) followed by water (20 ml), and stirred 10 minutes. The blue solution
was decanted and extracted with EtOAc (2.times.20 ml). The combined
organic layers were washed with water (20 ml), brine (20 ml), dried
(MgSO.sub.4), filtered and concentrated to afford the present title
product (129 mg, 90%); m.p. 120.degree.-122.degree. C.
EXAMPLE 74
5-[4-(3-Phenyl-2-propenoyl)phenylmethylene]thiazolidine-2,4-dione
A solution of 5-(4-acetylphenylmethylene)thiazolidine-2,4-dione (1.0 g, 4.0
mmol) and benzaldehyde (0.62 ml, 6.1 mmol) in 1N NaOH (14 ml) and methanol
(25 ml) was stirred for 1 hour at 0.degree. C. and then at room
temperature for 3 days, the precipitate was collected and dissolved in
water, and this solution was acidified with 2N HCl and extracted with
ethyl acetate (2.times.30 ml). The combined extracts were washed with
brine (30 ml), dried over sodium sulfate and concentrated in vacuo,
leaving the free acid form of title product (0.4 g, 29%) as a yellow
solid. The latter was converted to sodium salt according to the method of
Example 42.
EXAMPLE 75
Sodium Salt of 5-[4-(2-Phenoxy-1-hydroxyethyl)benzyl]thiazolidine-2,4-dione
Title product of Preparation 32 (1.5 g) was stirred in THF (50 ml) and 3.5%
HClO.sub.4 (30 ml) at room temperature for 18 hours. The solution was
extracted with ethyl acetate, and the extracts washed with saturated NaCl,
dried (MgSO.sub.4) and solvent removed in vacuo. The residue was purified
on silica gel using 1:1 hexane:ethyl acetate as eluant to afford 1.0 gram
of the free acid form of title product as an oil. The sodium salt was
prepared by combining the latter with a molar equivalent of NaOCH.sub.3 in
CH.sub.3 OH, and evaporation; m.p. 85.degree.-90.degree. C.
EXAMPLE 76
5-[4-(2-Phenoxyacetyl)benzyl]thiazolidine-2,4-dione
Title product of the preceding Example (1.0 mmol, 343 mg) was dissolved in
ether (10 ml) at 0.degree. C. Jones' Reagent (1.5 ml) was added and the
solution stirred for 1 hour. The mixture was diluted with ether, washed
with H.sub.2 O, saturated NaCl, dried (MgSO.sub.4) and the solvent removed
in vacuo to afford present title product as a solid; m.p.
170.degree.-174.degree. C.
Analysis calculated for C.sub.18 H.sub.15 O.sub.4 NS: C, 63.33; H, 4.43; N,
4.10%. Found: C, 62.89; H, 4.70; N, 4.17%.
PREPARATION 1
4-(Bromomethyl)benzenesulfonyl Chloride
p-Toluenesulfonyl chloride (0.52 mol, 100 g), N-bromosuccinimide (0.62 mol,
110.3 g), and benzoyl peroxide (5 g) were heated to reflux in carbon
tetrachloride (500 ml) for 1 hour. The mixture was filtered and the
filtrate was concentrated in vacuo. The residue was triturated with
isopropyl ether to afford 40.1 g of title product as a white solid; m.p.
70.degree.-73.degree. C.
PREPARATION 2
N-Benzyl-N-methyl-4-(bromomethyl)benzenesulfonamide
The title product of the preceding Preparation (37 mmol, 9.9 g) was
dissolved in methylene chloride (150 ml) at room temperature.
Benzylmethylamine (74 mmol, 9.0 g) dissolved in methylene chloride (25 ml)
was added dropwise over 20 minutes and the reaction mixture was stirred
for 1 hour. The solution was with water (2.times.100 ml), saturated sodium
chloride (100 ml), dried (Na.sub.2 SO.sub.4) and the solvent removed in
vacuo. The residue was recrystallized from ethyl acetate to afford 7.1 g
of the title sulfonamide; m.p. 122.degree.-123.degree. C.
Analysis calculated for C.sub.15 H.sub.16 O.sub.2 NSBr: C, 50.85; H, 4.55;
N, 3.95%. Found: C, 50.91; H, 4.60; N, 3.93%.
PREPARATION 3
N-Methyl-N-(2-phenylethyl)-4-(bromomethyl)benzenesulfonamide
Using a molar equivalent amount of N-methylphenethylamine in place of the
benzylmethylamine, the method of the preceding Preparation was used to
convert the sulfonyl chloride of Preparation 1 to present title product,
isolated as a gum.
PREPARATION 4
5-(Phenylmethylene)thiazolidine-2,4-dione
Benzaldehyde (0.78 mol, 82.8 g) and 2,4-thiazolidinedione (0.85 mol, 100 g)
were heated to reflux in a mixture of pyridine (215 ml) and
dimethylformamide (400 ml) for 18 hours. The reaction mixture was cooled
to 55.degree. C. and diluted with hexane (360 ml) and water (900 ml) and
stirred for 1 hour after cooling to room temperature. The product was
collected to afford 175 g of pale yellow solid; m.p.
246.degree.-248.degree. C.
PREPARATION 5
5-Benzylthiazolidine-2,4-dione
The title product of the preceding Preparation (0.12 mol, 25 g) was
hydrogenated in a Paar shaker at 50 psig for 18 hours at room temperature
using 10% Pd/C (25 g of 50 wt % H.sub.2 O) in tetrahydrofuran (750 ml) and
acetic acid (250 ml). The catalyst was removed by filtration and the
solvent removed in vacuo. The crude solid was recrystallized from
ethanol:water (1:2) to afford 15.4 g of pale grey crystals; m.p.
101.degree.-103.degree. C.
Analysis calculated for C.sub.10 H.sub.9 O.sub.2 NS: C, 57.95; H, 4.38; N,
6.76%. Found: C, 57.95; H, 4.30; N, 6.76%.
PREPARATION 6
4-[(Thiazolidine-2,4-dion-5-yl)methyl]benzenesulfonyl Chloride
Chlorosulfonic acid (5 ml) was cooled to 0.degree. C. and the
5-benzyl-2,4-thiazolidinedione prepared above (9.6 mmol, 2.0 g) was added
portionwise. The reaction mixture was stirred at room temperature for 0.5
hour and poured into ice (25 g). The solution was extracted with methylene
chloride (2.times.50 ml) and the organic layers were dried (Na.sub.2
SO.sub.4) and solvent removed in vacuo to afford title product which was
used without further purification.
PREPARATION 7
4-(2-Phenylethylthio)benzaldehyde
A mixture of 2-phenylethylmercaptan (72.3 mmol, 10.0 g),
4-bromobenzaldehyde (79.6 mmol, 14.7 g) and potassium carbonate (116 mmol,
16 g) were stirred in dimethylformamide (100 ml) at 110.degree. C. for 48
hours. The solution was cooled and diluted with water (200 ml). The
aqueous was extracted with ether (3.times.200 ml) and the combined ether
layers were dried (Na.sub.2 SO.sub.4) and concentrated in vacuo. The
residue was purified on silica gel using hexane:ethyl acetate (9:1) as
eluant to afford 11.7 g (67%) of present title product as a yellow oil.
.sup.1 H-NMR(CDCl.sub.3)delta(ppm): 3.1 (d of t), 7.2 (s), 7.3 (d), 7.7
(d), 9.9 (s). MS (m.sup.+) 242.
PREPARATION 8
4-(2-Phenylethylthio)acetophenone
A mixture of 2-phenylethylmercaptan (0.173 mol, 24 g), 4-bromoacetophenone
(0.19 mol, 38 g) and potassium carbonate (0.27 mol, 37 g) were heated in
dimethylformamide (50 ml) at 110.degree. C. for 24 hours. The reaction
mixture was cooled and diluted with water (500 ml). The solution was
extracted with ether (300 ml) and the ether was washed with water
(2.times.150 ml). The ether was dried (Na.sub.2 SO.sub.4) and removed in
vacuo. The crude product was purified on silica gel using hexane:ethyl
acetate (20:1) as eluant to afford 22.5 g of title product as an oil.
PREPARATION 9
4-[2-(4-Chlorophenyl)ethylthio]benzaldehyde
Title product was prepared from 2-(4-chlorophenyl)ethyl mercaptan and
4-bromobenzaldehyde according to the method of Preparation 7.
PREPARATION 10
4-(Benzylthio)benzaldehyde
Title product was prepared from benzyl mercaptan (145 mmol, 17.9 g) and
4-bromobenzaldehyde according to the method of Preparation 1 yielding 4 g
of purified product following chromatography on silica gel using 9:1
hexane:ethyl acetate as eluant.
PREPARATION 11
4-(3-Phenylpropylthio)benzaldehyde
By the method of Preparation 7, 3-phenylpropyl mercaptan (41.1 g) and
4-bromobenzaldehyde (53.7 g) were converted to 70 g of present title
product, isolated as an oil following chromatography on silica gel using
9:1 hexane:ethyl acetate as eluant; tlc Rf 0.4 (1:4 ethyl acetate:hexane).
PREPARATION 12
4-(2-Bromoethyl)benzaldehyde
To a solution of (2-bromoethyl)benzene (100 mmol, 18.5 g) in methylene
chloride (185 ml) at 0.degree. C. was added dropwise titanium
tetrachloride (200 mmol, 22 ml). The mixture was stirred for 10 minutes
and alpha,alpha-dichloromethyl methyl ether (100 mmol, 9 ml) was added
dropwise. The reaction mixture was stirred at room temperature for 1 hour
and poured into saturated NaHCO.sub.3 (1 liter). Ethyl acetate (750 ml)
was added and the solution was filtered through diatomaceous earth, the
organic layer separated, dried (Na.sub.2 SO.sub.4) and solvent removed in
vacuo. The residue was triturated with hexane to afford 8.7 g of title
product; m.p. 49.degree.-52.degree. C.
PREPARATION 13
4-[2-(Phenylthio)ethyl]benzaldehyde
Sodium hydride (31.1 mmol, 1.5 g of 50% dispersion in oil) was added to
dimethylformamide (15 ml) at room temperature. Benzenethiol (29.6 mmol,
3.3 g) was added (exothermic) and the mixture was stirred for 15 minutes.
The aldehyde of the preceding Preparation (29.6 mmol, 6.3 g) dissolved in
dimethylformamide (15 ml) was added dropwise and the reaction mixture was
heated at 110.degree. C. for 18 hours. The solution was cooled, diluted
with water (75 ml) and extracted with ether. The ether was washed with
water (2.times.75 ml, 1N NaOH (2.times.50 ml), water (2.times.50 ml), and
saturated NaCl (50 ml), dried (Na.sub.2 SO.sub.4) and removed in vacuo.
The crude oil was purified on silica gel using hexane:ethyl acetate (9:1)
to afford 5.1 g of title product as a yellow oil; tlc Rf 0.33 (1:5 ethyl
acetate:hexane).
PREPARATION 14
4-(Diethoxymethyl)benzyl Alcohol
To a solution of terephthalaldehyde mono(diethyl acetal) (1.9 ml, 9.6 mmol)
in methanol (35 ml) was added sodium borohydride (1.1 g, 28.8 mmol) while
cooling. After 5 minutes at room temperature the reaction was quenched
with water (50 ml) and the mixture was extracted with ethyl acetate
(2.times.50 ml). The combined extracts were washed with water and brine,
dried over sodium sulfate and concentrated in vacuo, leaving title product
as a colorless oil (1.81 g, 90%).
PREPARATION 15
1-(Methoxymethyl)-4-(diethoxymethyl)benzene
To title product of the preceding Preparation (1.51 g, 7.2 mmol) in dry THF
(5 ml) at 0.degree. C. was added potassium tert-butoxide (1.21 g, 11 mmol)
and after 5 minutes iodomethane (0.89 ml, 14 mmol). The solution was
stirred at room temperature for 1 hour, then diluted with water (15 ml)
and extracted with ether (2.times.10 ml). The combined organic layers were
washed with water (10 ml), brine (10 ml), dried over sodium sulfate and
concentrated in vacuo, leaving present title product (1.43 g, 89%) as a
colorless oil.
PREPARATION 16
4-(Methoxymethyl)benzaldehyde
A solution of title product of the preceding Preparation (1.3 g, 5.8 mmol)
in THF (12.5 ml) and 1N HCl (15 ml) was stirred at room temperature for 2
hours. Water (10 ml) was added and the mixture was extracted with
chloroform (2.times.15 ml). The combined extracts were washed with water
(15 ml) and brine (15 ml), dried over sodium sulfate and concentrated in
vacuo, leaving present title product (0.81 g, 93%) as a light yellow oil.
PREPARATION 17
4-[3-(3-Methoxyphenyl)-2-propenoyl]aniline
A solution of p-aminoacetophenone (14.9 g, 0.11 mol) and m-anisaldehyde
(10.0 g, 73 mmol) in methanol (500 ml) and 1N NaOH (260 ml) was stirred at
room temperature overnight. The precipitate was collected, the filtrate
was concentrated to 300 ml and the new precipitate was collected. The
combined solids were recrystallized from isopropanol to give present title
product as a yellow solid (10.4 g, 56%).
PREPARATION 18
4-[3-(3-Methoxyphenyl)propionyl]aniline
A solution of title product of the preceding Preparation (3.9 g, 15 mmol)
in ethanol (100 ml) containing 10% palladium on carbon (0.40 g) was
hydrogenated in a Parr shaker at 50 psig. The solution was filtered and
the filtrate was concentrated in vacuo. The product was dissolved in ethyl
acetate (150 ml) and this solution was washed with 1N HCl (2.times.75 ml),
water (75 ml) and brine (75 ml), dried over sodium sulfate and
concentrated in vacuo, leaving present title product (2.1 g, 53%) as an
oily solid.
PREPARATION 19
3-[4-[3-(3-Methoxyphenyl)propionyl]phenyl]-2-bromopropionic Acid
To an ice-cooled solution of title product of the preceding Preparation
(1.0 g, 3.9 mmol) in acetone (30 ml) and 48% HBr (2 ml) was added a
solution of sodium nitrite (0.27 g, 3.9 mmol) in water (2 ml). After 5
minutes acrylic acid (4 ml, 58 mmol) was added, followed after another 5
minutes by copper (I) bromide (5 mg). The solution was stirred for 20
minutes at room temperature, then diluted with water (30 ml), concentrated
to 30 ml and extracted with ethyl acetate (2.times.20 ml). The combined
extracts were washed with water (20 ml) and brine (20 ml), dried over
sodium sulfate and concentrated in vacuo to leave present title product as
a dark liquid.
PREPARATION 20
Methyl 4-(Dimethoxymethyl)benzoate
Methyl 4-formyl-benzoate (10.0 g, 60.9 mmol) was dissolved in a solution of
methanol (100 ml) and trimethyl orthoformate (5 ml). p-Toluenesulfonic
acid (100 mg) was added and the solution was refluxed overnight. After
cooling to room temperature, the reaction was quenched by the addition of
triethylamine (0.5 ml) and then poured into 5% aqueous NaHCO.sub.3 (100
ml). The aqueous layer was extracted with ether (3.times.100 ml) and the
combined organic solutions were dried (MgSO.sub.4) and concentrated to
give the methyl acetal ester (12.24 g, 96%). The material crystallized
upon standing (m.p. 28.degree.-30.degree. C.).
PREPARATION 21
Methyl 5-(Dimethoxymethyl)pyridine-2-carboxylate
To a solution of methyl 5-(dibromomethyl)pyridine-2-carboxylate (927 mg,
3.00 mmol) in methanol (10 ml) and trimethyl orthoformate (2 ml) was added
a solution AgNO.sub.3 (1.12 g, 6.6 mmol) in methanol (20 ml) over 15
minutes. After refluxing the reaction for 1 hour, it was cooled and poured
into a solution of NaHCO.sub.3 (0.84 g, 10 mmol) in water (50 ml)
containing a small amount of NaCl. The thick slurry was filtered through a
25-50 micron frit, and the filtrate concentrated to 10 ml and extracted
with ethyl acetate (3.times.10 ml). The combined organic layers were dried
(MgSO.sub.4), filtered and concentrated to give title product (550 mg,
96%).
PREPARATION 22
Methyl 2-(Dimethoxymethyl)pyridine-5-carboxylate
To a solution of methyl 2-formylpyridine-5-carboxylate (2.00 g, 12.1 mmol)
in methanol (20 ml) and trimethyl orthoformate (5 ml) was added H.sub.2
SO.sub.4 (conc., 1.5 ml). After refluxing overnight, the reaction was
cooled and concentrated to a thick slurry and then poured into saturated
NaHCO.sub.3 (50 ml). The latter was extracted with ether (3.times.30 ml)
and the combined organic layers dried (MgSO.sub.4) and concentrated to
afford title product (1.91 g, 75%).
PREPARATION 23
4-(4-Phenylbutyryl)benzaldehyde
To THF (30 ml) at -10.degree. C. was added diisopropylamine (8.01 ml, 57.1
mmol) followed by the dropwise addition of n-butyl lithium (2.0M in
hexane, 28.6 ml, 57.2 mmol) at a rate such that the internal temperature
was kept less than -5.degree. C. A solution of 4-phenylbutyric acid (4.70
g, 28.6 mmol) in THF (20 ml) was then added over 5 minutes followed by
hexamethylphosphoramide (4.98 ml, 26.8 mmol). After stirring for 30
minutes at room temperature, the reaction mixture was cooled to
-10.degree. C. and a solution of title product of Preparation 20 (5.0 g,
23.8 mmol) in THF (20 ml) was added dropwise. After stirring at room
temperature for 1 hour, the reaction was quenched into an equal volume of
3N HCl and stirred for an additional hour. After neutralization to pH 8
with NaHCO.sub.3, it was extracted with ether (3.times.50 ml) and the
combined organic layers were washed with water (50 ml), dried (MgSO.sub.4)
and concentrated to afford 3.95 g of a yellow oil. Chromatography on
silica gel with 3:1 hexane:ethyl acetate gave 2.57 g of a white solid
containing the desired title product and methyl 4-formylbenzoate.
PREPARATION 24
2-(3-Phenylpropionyl)pyridine-5-carbaldehyde
By the method of the preceding Preparation, 3-phenylpropionic acid and the
title product of Preparation 21 were converted to present title product in
19% yield.
PREPARATION 25
5-(3-Phenylpropionyl)pyridine-2-carbaldehyde
By the method of Preparation 23, 3-phenylpropionic acid and the title
product of Preparation 22 were converted to present title product in 26%
yield.
PREPARATION 26
2-(4-Diethoxymethylphenyl)ethanol
To a solution of 4-(diethoxymethyl)benzaldehyde (5.0 g, 24 mmol) in ether
(65 ml), cooled to -10.degree. C., was added dropwise a 1.5M toluene-THF
methylmagnesium bromide solution (64 ml, 96 mmol) at such a rate that the
temperature remains below 0.degree. C. After the addition the reaction was
quenched with saturated ammonium chloride (80 ml) and the solution was
diluted with water (50 ml) and extracted with ether (2.times.75 ml). The
combined extracts were washed with water (50 ml) and brine (50 ml), dried
over sodium sulfate and concentrated in vacuo, leaving present title
product (5.2 g, 97%) as an oil.
PREPARATION 27
4-(1-Hydroxyethyl)benzaldehyde
Title product of the preceding Preparation (5.2 g, 23 mmol) in THF (30 ml)
and 1N HCl (30 ml) was stirred at room temperature for 2 hours, then
diluted with water (30 ml) and extracted with chloroform (2.times.50 ml).
The combined extracts were washed with brine (30 ml), dried over sodium
sulfate and concentrated in vacuo, leaving present title product (3.2 g,
92%) as an oil.
PREPARATION 28
5-[4-(1-Hydroxyethyl)phenylmethylene]thiazolidine-2,4-dione
Title product of the preceding Example (3.2 g, 21 mmol) was combined with
2,4-thiazolidinedione (3.6 g, 31 mmol) and sodium acetate (5.1 g, 62 mmol)
and heated to 140.degree. C. for 1 hour. The yellow solid was triturated
with water for 30 minutes, then filtered and dried to yield present title
product (4.3 g, 81%).
PREPARATION 29
5-(4-Acetylphenylmethylene)thiazolidine-2,4-dione
Title product of the preceding Preparation (3.5 g, 14 mmol) in acetone (100
ml), cooled to 0.degree. C., was added dropwise to a 2.67M solution of
Jones' Reagent (10.5 ml, 28 mmol) over 10 minutes. The solution was
stirred for 2 hours at room temperature, then diluted with water (100 ml)
and extracted with ethyl acetate (3.times.60 ml). The combined extracts
were washed with water (2.times.60 ml) and brine (60 ml), dried over
sodium sulfate and concentrated in vacuo, leaving present title product
(3.1 g, 88%) as a yellow solid.
PREPARATION 30
alpha-Phenoxymethyl-4-benzyl Alcohol
Phenol (15.0 mmol, 1.41 g), alpha,4-dibromoacetophenone (15.0 mmol, 4.2 g)
and potassium carbonate (30.0 mmol, 4.15 g) were heated to reflux in
acetone (50 ml) for 8 hours. The solution was cooled, concentrated,
diluted with water (50 ml) and extracted with ether (2.times.100 ml). The
ether layers were combined, washed with 10% NaOH (50 ml) and then
saturated NaCl (50 ml), dried (MgSO.sub.4) to afford a mixture of title
product alpha-phenoxymethyl-4-benzyl alcohol and unreacted
dibromoacetophenone, all of which was dissolved in CH.sub.2 Cl.sub.2 (25
ml) and isopropanol (25 ml) and cooled to 0.degree. C. Sodium borohydride
(15.0 mmol, 570 mg) was added and the mixture was stirred for 1 hour.
Water (50 ml) was added and extracted with methylene chloride. The
organics were washed with saturated NaCl, dried (MgSO.sub.4) and
evaporated. The residue was purified on silica gel using 1:1
hexane:methylene chloride as eluant to afford 3.0 g of present title
product as an oil.
PREPARATION 31
4-(2-Phenoxy-1-(dimethyl-t-butylsilyloxy)ethyl)phenyl Bromide
Title product of the preceding Preparation (10.0 mmol, 2.93 g),
t-butyldimethylsilyl chloride (12.5 mmol, 1.9 g), and imidazole (25 mmol,
1.7 g) were stirred in DMF (40 ml) at room temperature for 36 hours. 10%
NaHCO.sub.3 (150 ml) was added and the solution was extracted with hexane
(2.times.200 ml) and the organics were washed with water, saturated NaCl,
dried (MgSO.sub.4) and evaporated. The product was purified on silica gel
using hexane:butyl chloride 4:1 as eluant to afford 2.5 g of present title
product as a colorless oil.
PREPARATION 32
5-[4-(2-Phenoxy-1-(dimethyl-t-butylsilyloxy)ethyl)benzyl]thiazolidine-2,4-d
ione
Title product of the preceding Preparation (6.1 mmol, 2.5 g) was dissolved
in THF (50 ml) and cooled to -78.degree. C. n-Butyllithium (6.7 mmol in
hexane) was added and the mixture stirred for 45 minutes. DMF (6.7 mmol,
0.52 ml) was added and the mixture was stirred at -78.degree. C. for 1
hour, following which 10% HCl (25 ml) was added and the mixture was warmed
to room temperature and extracted with ethyl acetate. The organics were
dried (MgSO.sub.4) and evaporated in vacuo to afford intermediate
4-(2-phenoxy-1-(dimethyl-t-butylsilyloxy)benzaldehyde, all of which was
intimately mixed with thiazolidine-2,4-dione (8.0 mmol) and sodium acetate
(15.0 mmol, 1.73 g) and the mixture fused at 160.degree. C. for 1 hour,
then cooled to room temperature. The solids were dissolved in ethyl
acetate (400 ml) and CH.sub.3 OH (25 ml), and washed with water and then
saturated NaCl, dried (MgSO.sub.4) and evaporated to afford intermediate
5-[4-(2-phenoxy-1-(dimethyl-t-butylsilyloxy)ethyl)phenylmethylene]thiazoli
dine-2,4-dione. The latter was dissolved in CH.sub.3 OH (100 ml) and
stirred with 3.5% Na/Hg (20 g) for 2 hours. The solids were removed by
filtration over diatomaceous earth and the solvent concentrated. The
residue was dissolved in ethyl acetate, washed with cold 10% HCl and then
saturated NaCl, dried (MgSO.sub.4) and evaporated. The residue was
purified on silica gel using 2:1 hexane:ethyl acetate to afford 1.6 g of
present title product as an oil.
PREPARATION 33
5-[(4-Acetylphenyl)methyl]thiazolidine-2,4-dione
A solution of 4-acetyl-alpha-bromobenzenepropanoic acid (87 g, 0.32 mol)
and thiourea (48.7 g, 0.64 mol) in sulfolane (100 ml) was heated to
105.degree.-110.degree. C. for 5 hours. To this mixture was added a 2N HCl
solution (162 ml) and the resulting solution was heated to
105.degree.-110.degree. C. overnight. After cooling and diluting with
water, the solid was collected, washed with water and dried (75 g, 94%);
m.p. 171.degree.-172.degree. C.
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